Boronic acid derivatives and therapeutic uses thereof

ABSTRACT

Disclosed herein are antimicrobial compounds compositions, pharmaceutical compositions, the use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents.

BACKGROUND Field of the Invention

The present invention relates to the fields of chemistry and medicine.More particularly, the present invention relates to boronic acidantimicrobial compounds, compositions, their preparation, and their useas therapeutic agents.

Description of the Related Art

Antibiotics have been effective tools in the treatment of infectiousdiseases during the last half-century. From the development ofantibiotic therapy to the late 1980s there was almost complete controlover bacterial infections in developed countries. However, in responseto the pressure of antibiotic usage, multiple resistance mechanisms havebecome widespread and are threatening the clinical utility ofantibacterial therapy. The increase in antibiotic resistant strains hasbeen particularly common in major hospitals and care centers. Theconsequences of the increase in resistant strains include highermorbidity and mortality, longer patient hospitalization, and an increasein treatment costs.

Various bacteria have evolved β-lactam deactivating enzymes, namely,β-lactamases, that counter the efficacy of the various β-lactamantibiotics. β-lactamases can be grouped into 4 classes based on theiramino acid sequences, namely, Ambler classes A, B, C, and D. Enzymes inclasses A, C, and D include active-site serine β-lactamases, and class Benzymes, which are encountered less frequently, are Zn-dependent. Theseenzymes catalyze the chemical degradation of β-lactam antibiotics,rendering them inactive. Some β-lactamases can be transferred within andbetween various bacterial strains and species. The rapid spread ofbacterial resistance and the evolution of multi-resistant strainsseverely limits β-lactam treatment options available.

The increase of class D β-lactamase-expressing bacterium strains such asAcinetobacter baumannii has become an emerging multidrug-resistantthreat. A. baumannii strains express A, C, and D class β-lactamases. Theclass D β-lactamases such as the OXA families are particularly effectiveat destroying carbapenem type β-lactam antibiotics, e.g., imipenem, theactive carbapenems component of Merck's Primaxin® (Montefour, K.; et al.Crit. Care Nurse 2008, 28, 15; Perez, F. et al. Expert Rev. Anti Infect.Ther. 2008, 6, 269; Bou, G.; Martinez-Beltran, J. Antimicrob. AgentsChemother. 2000, 40, 428. 2006, 50, 2280; Bou, G. et al, J. Antimicrob.Agents Chemother. 2000, 44, 1556). This has imposed a pressing threat tothe effective use of drugs in that category to treat and preventbacterial infections. Indeed the number of catalogued serine-based3-lactamases has exploded from less than ten in the 1970s to over 300variants. These issues fostered the development of five “generations” ofcephalosporins. When initially released into clinical practice,extended-spectrum cephalosporins resisted hydrolysis by the prevalentclass A β-lactamases, TEM-1 and SHV-1. However, the development ofresistant strains by the evolution of single amino acid substitutions inTEM-1 and SHV-1 resulted in the emergence of the extended-spectrumβ-lactamase (ESBL) phenotype.

New β-lactamases have recently evolved that hydrolyze the carbapenemclass of antimicrobials, including imipenem, biapenem, doripenem,meropenem, and ertapenem, as well as other β-lactam antibiotics. Thesecarbapenemases belong to molecular classes A, B, and D. Class Acarbapenemases of the KPC-type predominantly in Klebsiella pneumoniaebut now also reported in other Enterobacteriaceae, Pseudomonasaeruginosa and Acinetobacter baumannii. The KPC carbapenemase was firstdescribed in 1996 in North Carolina, but since then has disseminatedwidely in the US. It has been particularly problematic in the New YorkCity area, where several reports of spread within major hospitals andpatient morbidity have been reported. These enzymes have also beenrecently reported in France, Greece, Sweden, United Kingdom, and anoutbreak in Germany has recently been reported. Treatment of resistantstrains with carbapenems can be associated with poor outcomes.

The zinc-dependent class B metallo-β-lactamases are represented mainlyby the VIM, IMP, and NDM types. IMP and VIM-producing K. pneumonia werefirst observed in 1990s in Japan and 2001 in Southern Europe,respectively. IMP-positive strains remain frequent in Japan and havealso caused hospital outbreaks in China and Australia. Howeverdissemination of IMP-producing Enterobacteriaceae in the rest of theword appears to be somewhat limited. VIM-producing enterobacteria can befrequently isolated in Mediterranean countries, reaching epidemicproportions in Greece. Isolation of VIM-producing strains remains low inNorthern Europe and in the United States. In stark contrast, acharacteristic of NDM-producing K. pneumonia isolates has been theirrapid dissemination from their epicenter, the Indian subcontinent, toWestern Europe, North America, Australia and Far East. Moreover, NDMgenes have spread rapidly to various species other than K. pneumonia.

The plasmid-expressed class D carbapenemases belong to OXA-48 type.OXA-48 producing K. pneumonia was first detected in Turkey, in 2001. TheMiddle East and North Africa remain the main centers of infection.However, recent isolation of OXA-48-type producing organisms in India,Senegal and Argentina suggest the possibility of a global expansion.Isolation of OXA-48 in bacteria other than K. pneumonia underlines thespreading potential of OXA-48.

Treatment of strains producing any of these carbapenemases withcarbapenems can be associated with poor outcomes.

Another mechanism of 1-lactamase mediated resistance to carbapenemsinvolves combination of permeability or efflux mechanisms combined withhyper production of beta-lactamases. One example is the loss of a porincombined in hyperproduction of ampC beta-lactamase results in resistanceto imipenem in Pseudomonas aeruginosa. Efflux pump over expressioncombined with hyperproduction of the ampC β-lactamase can also result inresistance to a carbapenem such as meropenem.

Thus, there is a need for improved β-lactamase inhibitors.

SUMMARY

Some embodiments relate to a compound having the structure of structureof the formula I′ or II′:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each G is independently selected from the group consisting of        —C(O)R⁴, —C(O)(CH₂)₀₋₃SR³, —C(O)(CH₂)₁₋₃R⁴, —C(O)OR³,        —C(O)NR¹R², —C(O)NR¹OR³, —NR¹C(O)R⁴, —NR¹C(O)NR¹R², —NR¹C(O)OR³,        —NR¹S(O)₂R³, —NR¹S(O)₂NR¹R², —C(═NR¹)R⁴, —C(═NR¹)NR¹R²,        —NR¹CR⁴(═NR²), —NR¹C(═NR²)NR¹R², —S(O)₂R³, —S(O)(CH₂)₁₋₃R³,        —S(O)₂NR¹R², —S(O)₂NR¹OR³, —NR¹S(O)₂NR¹OR³, —CN, —OR¹, —SR¹,        —NR¹R², optionally substituted C₁₋₁₀ alkyl, optionally        substituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl,        optionally substituted C₃₋₇ carbocyclyl, optionally substituted        5-10 membered heterocyclyl, optionally substituted C₆₋₁₀aryl,        optionally substituted 5-10 membered heteroaryl, optionally        substituted C₃₋₇carbocyclyl-C₁₋₆alkyl, optionally substituted        5-10 membered heterocyclyl-C₁₋₆alkyl, optionally substituted        C₆₋₁₀aryl-C₁₋₆alkyl, and optionally substituted 5-10 membered        heteroaryl-C₁₋₆alkyl;    -   Y¹ is selected from the group consisting of CR¹ and N;    -   each Y² is independently selected from the group consisting of        —S—, —S(O)—, —S(O)₂—, —O—, —CR¹R²—, and —NR²—, or Y²—(CH₂)_(n)-G        is CH₃;    -   Y⁴ is selected from the group consisting of —O—, —S—, and —NR¹—;    -   Y⁵ is selected from the group consisting of —OH, —SH, and —NHR¹;    -   Y⁶ is selected from the group consisting of —OH, optionally        substituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R²,    -   Q¹ and Q² is each indecently H or —Y²—(CH₂)_(n)-G;    -   each n is independently an integer from 0 to 3;    -   m is 0 or 1;    -   A is selected from the group consisting of C₃₋₁₀ carbocyclyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered        heterocyclyl;    -   each R¹, R², R³, and R⁴ are independently selected from —H,        halogen, optionally substituted C₁₋₄alkyl, optionally        substituted O—C₁₋₄alkyl, optionally substituted C₃₋₇        carbocyclyl, optionally substituted 4-10 membered heterocyclyl,        optionally substituted C₆₋₁₀aryl, and optionally substituted        5-10 membered heteroaryl;    -   R⁵ is present 1 to 5 times and each R⁵ is independently selected        from the group consisting of H, OH, halogen, CN, —C(O)OR¹;        —C(O)NR¹R²; —C(O)NR¹OR²; —NR¹C(O)R²; —NR¹C(O)NR²R³; —NR¹C(O)OR²;        —NR¹S(O)₂R²; —NR¹S(O)₂NR²R³; —C(═NR¹)R²; —C(═NR¹)NR²R³;        —NR¹CR²(═NR³); —NR¹C(═NR²)NR³R⁴; —S(O)(CH₂)₁₋₃R⁴, —S(O)₂NR¹R²,        —S(O)₂NR¹OR³, —NR¹S(O)₂NR¹OR³, optionally substituted C₂-C₆        alkenyl, optionally substituted C₂-C₆ alkynyl, optionally        substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₇        carbocyclyl, optionally substituted 5-10 membered heterocyclyl,        optionally substituted C₆₋₁₀aryl, optionally substituted 5-10        membered heteroaryl, cyano, C₁-C₆ alkoxy(C₁-C₆)alkyl, aryloxy,        sulfhydryl (mercapto), and —(CH₂)_(p)—Y³—(CH₂)_(q)M′;    -   p and q are each independently 0, 1, or 2;    -   Y³ is selected from the group consisting of —S—, —S(O)—,        —S(O)₂—, —O—, —CR¹R²—, and —NR¹—;    -   M′ is selected from the group consisting of halogen, cycano,        —OH, —C(O)NR¹R²; —C(O)NR¹OR²; —NR¹C(O)R²; —NR¹C(O)NR²R³;        —NR¹C(O)OR²; —NR¹S(O)₂R²; —NR¹S(O)₂NR²R³; —C(═NR¹)R²;        —C(═NR¹)NR²R³; —NR¹CR²(═NR³); —NR¹C(═NR²)NR³R⁴; —S(O)₂R¹,        —S(O)₂NR¹R², —S(O)₂NR¹OR³, C₁₋₄ alkyl optionally substituted        with 0-2 substituents selected from the group consisting of        —OR¹, —CN, —NR¹R², -heterocyclyl, halogen, —C(O)NR¹R², and        —NR¹C(O)R²; C₂₋₄ alkenyl optionally substituted with 0-2        substituents selected from the group consisting of C₁₋₄ alkyl,        —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,        —(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and —NR¹C(O)R²;        C₂₋₄ alkynyl optionally substituted with 0-2 substituents        selected from the group consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR¹,        —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen,        —C(O)NR¹R², and —NR¹C(O)R²; C₆₋₁₀ aryl optionally substituted        with 0-2 substituents selected from the group consisting of C₁₋₄        alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,        —(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and —NR¹C(O)R²;        C₃₋₇ carbocyclyl optionally substituted with 0-2 substituents        selected from the group consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR¹,        —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen,        —C(O)NR¹R², and —NR¹C(O)R²; 5-10 membered heteroaryl optionally        substituted with 0-2 substituents selected from the group        consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN,        —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and        —NR¹C(O)R²; and 3-10 membered heterocyclyl optionally        substituted with 0-2 substituents selected from the group        consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN,        —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and        —NR¹C(O)R²;    -   R⁶ is selected from the group consisting of is selected from the        group consisting of —H, halogen, optionally substituted —C₁₋₆        alkyl, —OH, —C(O)OR, —P(O)(OR)₂, P(O)(OR)R¹, optionally        substituted —O—C₁₋₆ alkyl, —NR¹R², —N(OR³)R², optionally        substituted —S—C₁₋₆ alkyl, —C(O)NR¹R², —S(O)₂NR¹R², CN,        optionally substituted —S(O)—C₁₋₆ alkyl, optionally substituted        —S(O)₂—C₁₋₆ alkyl, and a carboxylic acid isostere;    -   R is selected from —H, —C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₁₋₉alkyl,        —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl,        —CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl, —CR¹⁰R¹¹OC(O)NR¹⁰C₁₋₉alkyl,        —CR¹⁰R¹¹OC(O)NR¹⁰C₆₋₁₀aryl, and

-   -   R⁷ is selected from the group consisting of OH, optionally        substituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R²; and

R¹⁰ and R¹¹ are independently selected from the group consisting of —H,optionally substituted C₁₋₄alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 5-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl.

A compound having the structure of the Formula (I) or (II):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each G is independently selected from the group consisting of        —C(O)R⁴, —C(O)(CH₂)₀₋₃SR³, C(O)(CH₂)₁₋₃R⁴, —C(O)OR³, —C(O)NR¹R²,        —C(O)NR¹OR³, —NR¹C(O)R⁴, —NR¹C(O)NR¹R², —NR¹C(O)OR³,        —NR¹S(O)₂R³, —NR¹S(O)₂NR¹R², —C(═NR¹)R⁴, —C(═NR¹)NR¹R²,        —NR¹CR⁴(═NR²), —NR¹C(═NR²)NR¹R², —S(O)₂R³, optionally        substituted C₁₋₁₀ alkyl, optionally substituted C₂₋₁₀alkenyl,        optionally substituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇        carbocyclyl, optionally substituted 5-10 membered heterocyclyl,        optionally substituted C₆₋₁₀aryl, optionally substituted 5-10        membered heteroaryl, optionally substituted        C₃₋₇carbocyclyl-C₁₋₆alkyl, optionally substituted 5-10 membered        heterocyclyl-C₁₋₆alkyl, optionally substituted        C₆₋₁₀aryl-C₁₋₆alkyl, and optionally substituted 5-10 membered        heteroaryl-C₁₋₆alkyl;    -   Y¹ is selected from the group consisting of CR¹ and N;    -   each Y² is independently selected from the group consisting of        —S—, —S(O)—, —S(O)₂—, —O—, —CR¹R²—, and —NR²—;    -   Y⁴ is selected from the group consisting of —O—, —S—, and —NR¹—;    -   Y⁵ is selected from the group consisting of —OH, —SH, and —NHR¹;    -   Y⁶ is selected from the group consisting of —OH, optionally        substituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R², Q is H or        —Y²—(CH₂)_(n)-G;    -   each n is independently an integer from 0 to 3;    -   m is 0 or 1;    -   A is selected from the group consisting of C₃₋₁₀ carbocyclyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered        heterocyclyl;    -   each R¹, R², R³, and R⁴ are independently selected from —H,        optionally substituted C₁₋₄alkyl, optionally substituted C₃₋₇        carbocyclyl, optionally substituted 4-10 membered heterocyclyl,        optionally substituted C₆₋₁₀aryl, and optionally substituted        5-10 membered heteroaryl;    -   R⁵ is present 1 to 5 times and each R⁵ is independently selected        from the group consisting of H, OH, halogen, —CF₃, optionally        substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,        optionally substituted C₁-C₆ heteroalkyl, optionally substituted        C₃-C₇ carbocyclyl, optionally substituted 5-10 membered        heterocyclyl, optionally substituted C₆₋₁₀aryl, optionally        substituted 5-10 membered heteroaryl, cyano, C₁-C₆        alkoxy(C₁-C₆)alkyl, aryloxy, sulfhydryl (mercapto), and        —(CH₂)_(p)—Y³—(CH₂)_(q)M′;    -   p and q are each independently 0 or 1;    -   Y³ is selected from the group consisting of —S—, —S(O)—,        —S(O)₂—, —O—, —CH₂—, and —NR¹—;    -   M′ is selected from the group consisting of —C(O)NR¹R²;        —C(O)NR¹OR²; —NR¹C(O)R²; —NR¹C(O)NR²R³; —NR¹C(O)OR²;        —NR¹S(O)₂R²; —NR¹S(O)₂NR²R³; —C(═NR¹)R²; —C(═NR¹)NR²R³;        —NR¹CR²(═NR³); —NR¹C(═NR²)NR³R⁴; C₁₋₄ alkyl optionally        substituted with 0-2 substituents selected from the group        consisting, —OR¹, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R²;        C₆₋₁₀aryl optionally substituted with 0-2 substituents selected        from the group consisting of C₁₋₄ alkyl, —OR¹, —NR¹R², halogen,        —C(O)NR¹R², and —NR¹C(O)R²; C₃₋₇ carbocyclyl optionally        substituted with 0-2 substituents selected from the group        consisting of C₁₋₄ alkyl, —OR¹, —NR¹R², halogen, —C(O)NR¹R², and        —NR¹C(O)R²; 5-10 membered heteroaryl optionally substituted with        0-2 substituents selected from the group consisting of C₁₋₄        alkyl, —OR¹, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R²; and        3-10 membered heterocyclyl optionally substituted with 0-2        substituents selected from the group consisting of C₁₋₄ alkyl,        —OR¹, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R²;    -   R⁶ is selected from the group consisting of is selected from the        group consisting of —H, halogen, optionally substituted —C₁₋₆        alkyl, —OH, —C(O)OR, optionally substituted —O—C₁₋₆ alkyl,        —NR¹R², —N(OR³)R², optionally substituted —S—C₁₋₆ alkyl,        —C(O)NR¹R², —S(O)₂NR¹R², CN, optionally substituted —S(O)—C₁₋₆        alkyl, optionally substituted —S(O)₂—C₁₋₆ alkyl, and a        carboxylic acid isostere;    -   R is selected from —H, —C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₁₋₉alkyl,        —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl,        —CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl and

-   -   R⁷ is selected from the group consisting of OH, optionally        substituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R²; and    -   R¹⁰ and R¹¹ are independently selected from the group consisting        of —H, optionally substituted C₁₋₄alkyl, optionally substituted        C₃₋₇ carbocyclyl, optionally substituted 5-10 membered        heterocyclyl, optionally substituted C₆₋₁₀aryl, and optionally        substituted 5-10 membered heteroaryl.

Some embodiments relate to compound having the structure of the formulaIII′ or IV′:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   A is selected from the group consisting of C₃₋₁₀ carbocyclyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered        heterocyclyl;    -   m is 0, 1 or 2;    -   Y⁷ is selected from the group consisting of —CH₂—, —O—, —S— and        —NR¹—;    -   n is 1, 2 or 3;    -   Q¹ and Q² are H;    -   each R⁷ is independently selected from the group consisting of        OH, optionally substituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR)R²;        and    -   Y⁴ is selected from the group consisting of —O—, —S—, and —NR¹—;    -   Y⁵ is selected from the group consisting of —OH, —SH, and —NHR¹;    -   Y⁶ is selected from the group consisting of —OH, optionally        substituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR¹)R²;    -   each R¹, R², R³ and R⁴ are independently selected from —H,        halogen, optionally substituted C₁₋₄alkyl, optionally        substituted O—C₁₋₄alkyl, optionally substituted C₃₋₇        carbocyclyl, optionally substituted 4-10 membered heterocyclyl,        optionally substituted C₆₋₁₀aryl, and optionally substituted        5-10 membered heteroaryl;    -   R⁵ is present 1 to 5 times and each R⁵ is independently selected        from the group consisting of H, OH, halogen, —C(O)OR¹;        —C(O)NR¹R²; —C(O)NR¹OR²; —C(═NR¹)R²; —C(═NR¹)NR²R³; —NR¹C(O)R²;        —NR¹C(O)NR²R³; —NR¹C(O)OR²; —NR¹S(O)₂R²; —NR¹S(O)₂NR²R³;        —NR¹CR²(═NR³); —NR¹C(═NR²)NR³R⁴; —S(O)(CH₂)₁₋₃R⁴, S(O)₂NR¹R²,        —S(O)₂NR¹OR³, —NR¹S(O)₂NR¹OR³, optionally substituted C₂-C₆        alkenyl, optionally substituted C₂-C₆ alkynyl, optionally        substituted C₁-C₆ heteroalkyl, optionally substituted C₃-C₇        carbocyclyl, optionally substituted 5-10 membered heterocyclyl,        optionally substituted C₆₋₁₀aryl, optionally substituted 5-10        membered heteroaryl, cyano, C₁-C₆ alkoxy(C₁-C₆)alkyl, aryloxy,        sulfhydryl (mercapto), and —(CH₂)_(p)—Y³—(CH₂)_(q)M′;    -   p and q are each independently 0, 1, or 2;    -   Y³ is selected from the group consisting of —S—, —S(O)—,        —S(O)₂—, —O—, —CR¹R², and —NR¹—;    -   M′ is selected from the group consisting of halogen, cyano, —OH,        —C(O)NR¹R²; —C(O)NR¹OR²; —NR¹C(O)R²; —NR¹C(O)NR²R³; —NR¹C(O)OR²;        —NR¹S(O)₂R²; —NR¹S(O)₂NR²R³; —C(═NR¹)R²; —C(═NR¹)NR²R³; —NR¹CR²        (═NR³); —NR¹C(═NR²)NR³R⁴; —S(O)₂R¹, —S(O)₂NR¹R², —S(O)₂NR¹OR³,        C₁₋₄ alkyl optionally substituted with 0-2 substituents selected        from the group consisting of —OR¹, —CN, —NR¹R², -heterocyclyl,        halogen, —C(O)NR¹R², and —NR¹C(O)R²; C₂₋₄ alkenyl optionally        substituted with 0-2 substituents selected from the group        consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN,        —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and        —NR¹C(O)R²; C₂₋₄ alkynyl optionally substituted with 0-2        substituents selected from the group consisting of C₁₋₄ alkyl,        —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,        —(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and —NR¹C(O)R²;        C₆₋₁₀ aryl optionally substituted with 0-2 substituents selected        from the group consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR¹,        —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen,        —C(O)NR¹R², and —NR¹C(O)R²; C₃₋₇ carbocyclyl optionally        substituted with 0-2 substituents selected from the group        consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN,        —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and        —NR¹C(O)R²; 5-10 membered heteroaryl optionally substituted with        0-2 substituents selected from the group consisting of C₁₋₄        alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,        —(CH₂)₀₋₄-heterocyclyl halogen, —C(O)NR¹R², and —NR¹C(O)R²; and        3-10 membered heterocyclyl optionally substituted with 0-2        substituents selected from the group consisting of C₁₋₄ alkyl,        —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,        —(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and —NR¹C(O)R²;    -   R⁶ is selected from the group consisting of H, halogen,        optionally substituted —C₁₋₆ alkyl, —OH, —C(O)OR, —P(O)(OR)₂,        P(O)(OR)R¹, optionally substituted —O—C₁₋₆ alkyl, —NR¹R²,        —N(OR¹)R², optionally substituted —S—C₁₋₆ alkyl, —C(O)NR¹R²,        —S(O)₂NR¹R², CN, optionally substituted —S(O)—C₁₋₆ alkyl,        optionally substituted —S(O)₂—C₁₋₆ alkyl, and a carboxylic acid        isostere;    -   R is selected from —H, alkali metal, NH₄ ⁺, —C₁₋₉alkyl,        —CR¹⁰R¹⁰OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl,        —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl, —CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl,        —CR¹⁰R¹¹OC(O)NR¹⁰C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)NR¹⁰C₆₋₁₀aryl, and

-   -   R¹⁰ and R¹¹ are independently selected from the group consisting        of —H, optionally substituted C₁₋₄alkyl, optionally substituted        C₃₋₇ carbocyclyl, optionally substituted 5-10 membered        heterocyclyl, optionally substituted C₆₋₁₀aryl, and optionally        substituted 5-10 membered heteroaryl.

Some embodiments relate to a compound having the structure of Formula(III) or (IV):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   A is selected from the group consisting of C₃₋₁₀ carbocyclyl,        C₆₋₁₀aryl, 5-10 membered heteroaryl, and 5-10 membered        heterocyclyl;    -   m is 0, 1 or 2;    -   Y⁷ is selected from the group consisting of CH₂, O, S and NH;    -   n¹ is 1, 2 or 3;    -   each R⁷ is independently selected from the group consisting of        OH, optionally substituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR¹)R²;        and    -   Y⁴ is selected from the group consisting of —O—, —S—, and —NR¹—;    -   Y⁵ is selected from the group consisting of —OH, —SH, and —NHR¹;    -   Y⁶ is selected from the group consisting of —OH, optionally        substituted —O—C₁₋₆ alkyl, —NR¹R², and —N(OR¹)R²;    -   each R¹, R², R³ and R⁴ are independently selected from —H,        optionally substituted C₁₋₄alkyl, optionally substituted C₃₋₇        carbocyclyl, optionally substituted 4-10 membered heterocyclyl,        optionally substituted C₆₋₁₀aryl, and optionally substituted        5-10 membered heteroaryl;    -   R⁵ is present 1 to 5 times and each R⁵ is independently selected        from the group consisting of H, OH, halogen, —CF₃, optionally        substituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,        optionally substituted C₁-C₆ heteroalkyl, optionally substituted        C₃-C₇ carbocyclyl, optionally substituted 5-10 membered        heterocyclyl, optionally substituted C₆₋₁₀aryl, optionally        substituted 5-10 membered heteroaryl, cyano, C₁-C₆        alkoxy(C₁-C₆)alkyl, aryloxy, sulfhydryl (mercapto), and        —(CH₂)_(p)—Y³—(CH₂)_(q)M′;    -   p and q are each independently 0 or 1;    -   Y³ is selected from the group consisting of —S—, —S(O)—,        —S(O)₂—, —O—, —CH₂—, and —NR¹—;    -   M′ is selected from the group consisting of —C(O)NR¹R²;        —C(O)NR¹OR²; —NR¹C(O)R²; —NR¹C(O)NR²R³; —NR¹C(O)OR²;        —NR¹S(O)₂R²; —NR¹S(O)₂NR²R³; —C(═NR¹)R²; —C(═NR¹)NR²R³;        —NR¹CR²(═NR³); —NR¹C(═NR²)NR³R⁴; C₁₋₄ alkyl optionally        substituted with 0-2 substituents selected from the group        consisting, —OR, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R²;        C₆₋₁₀ aryl optionally substituted with 0-2 substituents selected        from the group consisting of C₁₋₄ alkyl, —OR¹, —NR¹R², halogen,        —C(O)NR¹R², and —NR¹C(O)R²; C₃₋₇ carbocyclyl optionally        substituted with 0-2 substituents selected from the group        consisting of C₁₋₄ alkyl, —OR¹, —NR¹R², halogen, —C(O)NR¹R², and        —NR¹C(O)R²; 5-10 membered heteroaryl optionally substituted with        0-2 substituents selected from the group consisting of C₁₋₄        alkyl, —OR¹, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R²; and        3-10 membered heterocyclyl optionally substituted with 0-2        substituents selected from the group consisting of C₁₋₄ alkyl,        —OR¹, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R²;    -   R⁶ is selected from the group consisting of H, halogen,        optionally substituted —C₁₋₆ alkyl, —OH, —C(O)OR, optionally        substituted —O—C₁₋₆ alkyl, —NR¹R², —N(OR¹)R², optionally        substituted —S—C₁₋₆ alkyl, —C(O)NR¹R², —S(O)₂NR¹R², CN,        optionally substituted —S(O)—C₁₋₆ alkyl, optionally substituted        —S(O)₂—C₁₋₆ alkyl, and a carboxylic acid isostere;    -   R is selected from —H, alkali metal, NH₄ ⁺, —C₁₋₉alkyl,        —CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl,        —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl, —CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl and

-   -   R¹⁰ and R¹¹ are independently selected from the group consisting        of —H, optionally substituted C₁₋₄alkyl, optionally substituted        C₃₋₇ carbocyclyl, optionally substituted 5-10 membered        heterocyclyl, optionally substituted C₆₋₁₀aryl, and optionally        substituted 5-10 membered heteroaryl.

Some embodiments relate to a compound having the structure selected fromthe group consisting of

and pharmaceutically acceptable salts thereof.

Other embodiments disclosed herein include a pharmaceutical compositioncomprising a therapeutically effective amount of a compound disclosedherein and a pharmaceutically acceptable excipient.

Other embodiments disclosed herein include a method of treating orpreventing a bacterial infection, comprising administering to a subjectin need thereof a compound disclosed herein.

DETAILED DESCRIPTION

In some embodiments, compounds that contain a boronic acid moiety areprovided that act as antimicrobial agents and/or as potentiators ofantimicrobial agents Various embodiments of these compounds includecompounds having the structures of Formula (I) as described above orpharmaceutically acceptable salts thereof.

In some embodiments, the compound described herein has the structure ofFormula (I′) or a pharmaceutically acceptable salt thereof. In someembodiments, the compound described herein has the structure of Formula(II′) or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound described herein has the structure ofFormula (I) or a pharmaceutically acceptable salt thereof. In someembodiments, the compound described herein has the structure of Formula(II) or a pharmaceutically acceptable salt thereof.

In some embodiments, Q¹ and Q² are deuterium. In some embodiments, Q¹ ishydrogen and Q² is deuterium. In some embodiments, Q¹ is —Y²—(CH₂)_(n)-Gand Q² is deuterium. In some embodiments, Q¹ is —Y²—(CH₂)_(n)-G and Q²is hydrogen.

In some embodiments, Q is —Y²—(CH₂)_(n)-G. In some embodiments, Q is H.

Some embodiments of compounds of Formula (I′) or (I) include compoundshaving the structure of Formula (I-1)

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   G is selected from the group consisting of —C(O)R⁴,        —C(O)(CH₂)₀₋₃SR³, —C(O)OR³, —C(O)NR¹R², —C(O)NR¹OR³, —NR¹C(O)R⁴,        —NR¹C(O)NR¹R², —NR¹C(O)OR³, —NR¹S(O)₂R³, —NR¹S(O)₂NR¹R²,        —C(═NR¹)R⁴, —C(═NR¹)NR¹R², NR¹CR⁴(═NR²), —NR¹C(═NR²)NR¹R²,        —S(O)₂R³, optionally substituted C₁₋₁₀ alkyl, optionally        substituted C₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl,        optionally substituted C₃₋₇ carbocyclyl, optionally substituted        5-10 membered heterocyclyl, optionally substituted C₆₋₁₀aryl,        optionally substituted 5-10 membered heteroaryl, optionally        substituted C₃₋₇carbocyclyl-C₁₋₆alkyl, optionally substituted        5-10 membered heterocyclyl-C₁₋₆alkyl, optionally substituted        C₆₋₁₀aryl-C₁₋₆alkyl, and optionally substituted 5-10 membered        heteroaryl-C₁₋₆alkyl;    -   each R¹, R², R³, and R⁴ are independently selected from —H,        optionally substituted C₁₋₄alkyl, optionally substituted C₃₋₇        carbocyclyl, optionally substituted 5-10 membered heterocyclyl,        optionally substituted C₆₋₁₀aryl, and optionally substituted        5-10 membered heteroaryl; and    -   R is selected from —H, —C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₁₋₉alkyl,        —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, and

Some embodiments of compounds of Formula (I-A), Formula (I) or Formula(I-1) include compounds having the structure of Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; andJ, L, and M are each independently selected from the group consisting ofCR⁵ and N.

Some embodiments of compounds of Formula (I′), Formula (I), Formula(I-1), or Formula (Ia) or their pharmaceutically acceptable salts havethe following stereochemistry as shown in the structure of formula (Ib)

Some embodiments of compounds of Formula (I′), Formula (I), Formula(I-1), or Formula (Ia) or their pharmaceutically acceptable salts havethe following stereochemistry as shown in the structure of formula (Ic)

Some embodiments of compounds of Formula (II′) or Formula (II) includecompounds having the structure of Formula (IIa):

-   -   or a pharmaceutically acceptable salt thereof, wherein: n is 0        or 1; and J, L, and M are each independently selected from the        group consisting of CR⁵ and N.

Some embodiments of compounds of Formula (II′), Formula (II) or Formula(IIa) or their pharmaceutically acceptable salts include compoundshaving the structure of Formula (IIb):

Some embodiments of compounds of Formula (II′), Formula (II), Formula(IIa), or Formula (IIb) or their pharmaceutically acceptable saltsinclude compounds having the structure of Formula (IIc):

In some embodiments of Formula (I′), (I), (I-1), (Ia), (Ib) (Ic), (II′),(II), (IIa), (IIb), or (IIc), Y² is selected from the group consistingof —S—, —SO₂—, —O—, or —NH—. In some embodiments of Formula (I′), (I),(I-1), (Ia), (Ib) (Ic), (II), (IIa), (IIb), or (IIc), Y² is selectedfrom the group consisting of —S—, —SO₂—, —O—, or —NR¹—.

In some embodiments of Formula (I′) or (I), Y⁴ is —O—.

In some embodiments of Formula (Ia), (Ib) (Ic), (IIa), (IIb), or (IIc),M is N. In some embodiments of Formula (Ia), (Ib) (Ic), (IIa), (IIb), or(IIc), M is CR⁵. In some embodiments of Formula (Ia), (Ib) (Ic), (IIa),(IIb), or (IIc), J and L are each independently CR⁵. In someembodiments, J and L are CH. In some embodiments of Formula (Ia), (Ib)(Ic), (IIa), (IIb), or (IIc), J is N. In some embodiments of Formula(Ia), (Ib) (Ic), (IIa), (IIb), or (IIc), L and M are each independentlyCR⁵. In some embodiments of Formula (Ia), (Ib) (Ic), (IIa), (IIb), or(IIc), L is N. In some embodiments of Formula (Ia), (Ib) (Ic), (IIa),(IIb), or (IIc), J and M are each independently CR⁵.

In some embodiments of Formula (I), R⁷ is —OH.

Some embodiments of the compounds of Formula (I′) or Formula (I) ortheir pharmaceutically acceptable salts can have the structure ofFormula (Id):

In some embodiments of Formula (I′), (II′), (I), (II), (Ia), (Ib) (Ic),(Id), (IIa), (IIb), or (IIc), Y² is —O— or —S—; G is selected from thegroup consisting of C₁₋₄alkyl, phenyl, imidazole, pyrazole, triazole,tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole,isothiazole, pyridine, pyrazine, pyrimidine, pyridazine, and pyrazine,each optionally substituted by 0-2 substituents selected from the groupconsisting of hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl, aryloxy,halo(C₁-C₆)alkoxy, amino, C-amido, and N-amido; and J, L and M are CR⁵.

In some embodiments of Formula (I′), (II′), (I), (II), (Ia), (Ib), (Ic),(Id), (IIa), (IIb), or (IIc), G is C₁₋₄alkyl. In some embodiments, G is—CH₃.

In some embodiments of Formula (I′), (II′), (I), (II), (Ia), (Ib), (Ic),(Id), (IIa), (IIb), or (IIc), G is thiadiazole optionally substitutedwith amino. In some embodiments, G is

In some embodiments of Formula (I′), (II′), (I), (II), (Ia), (Ib), (Ic),(Id), (IIa), (IIb), or (IIc), M is CR⁵; and each R⁵ is independentlyselected from the group consisting of —H, —C₁₋₄alkyl, and halogen, —CF₃,and —(CH₂)_(p)—Y³—(CH₂)_(q)M′.

In some embodiments, R⁵ is CN, —C(O)OR¹; —C(O)NR¹R²; —C(O)NR¹OR²;—NR¹C(O)R²; —NR¹C(O)NR²R³; —NR¹C(O)OR²; —NR¹S(O)₂R²; —NR¹S(O)₂NR^(2R3);—C(═NR¹)R²; —C(═NR¹)NR²R³; —NR¹CR²(═NR³); —NR¹C(═NR²)NR³R⁴;—S(O)(CH₂)₁₋₃R⁴, —S(O)₂NR¹R², —S(O)₂NR¹OR³, or —NR¹S(O)₂NR¹OR³. In someembodiments, R⁵ is —(CH₂)_(p)—Y³—(CH₂)_(q)M′.

In some embodiments, p and q are each independently 0, 1, or 2. In someembodiments, p and q are each independently 0 or 1.

In some embodiments of Formula (I′), (II′), (I), (II), (Ia), (Ib), (Ic),(Id), (IIa), (IIb), or (IIc), R⁵ is —(CH₂)_(p)—Y³—(CH₂)_(q)M′; m is 0; pis 0; Y³ is S or O; and M′ is hydrogen; hydroxyl; C₁-C₄ alkyl optionallysubstituted with one or more substituents selected from the groupconsisting of —O—C₁-C₆alkyl, —S—C₁-C₆alkyl, amino, —C(O)-amino,—S(O)₂-amino, hydroxy, cyano, azido, and halogen; C₃₋₁₀ cycloalkyloptionally substituted with one or more substituents selected from thegroup consisting of C₁-C₆alkyl, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl, amino,—C(O)-amino, —S(O)₂-amino, hydroxy, cyano, azido, and halogen; C₆-C₁₀aryl optionally substituted with one or more substituents selected fromthe group consisting of C₁-C₆alkyl, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl, amino,—C(O)-amino, —S(O)₂-amino, hydroxy, cyano, azido, and halogen; 5 to 10membered heteroaryl optionally substituted with one or more substituentsselected from the group consisting of C₁-C₆alkyl, —O—C₁-C₆alkyl,—S—C₁-C₆alkyl, amino, —C(O)-amino, —S(O)₂-amino, hydroxy, cyano, azido,and halogen; and 4 to 10 membered heterocyclyl optionally substitutedwith one or more substituents selected from the group consisting ofC₁-C₆alkyl, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl, amino, —C(O)-amino,—S(O)₂-amino, hydroxy, cyano, azido, and halogen.

In some embodiments, M′ is selected from the group consisting ofhalogen, cycano, —OH, —S(O)₂R¹, —S(O)₂NR¹R², —S(O)₂NR¹OR³, C₁₋₄ alkyloptionally substituted with 0-2 substituents selected from the groupconsisting of —OR¹, —CN, —NR¹R², -heterocyclyl, halogen, —C(O)NR¹R², and—NR¹C(O)R²; C₂₋₄ alkenyl optionally substituted with 0-2 substituentsselected from the group consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR¹,—(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen,—C(O)NR¹R², and —NR¹C(O)R²; C₂₋₄ alkynyl optionally substituted with 0-2substituents selected from the group consisting of C₁₋₄ alkyl,—(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl,halogen, —C(O)NR¹R², and —NR¹C(O)R²; C₆₋₁₀ aryl optionally substitutedwith 0-2 substituents selected from the group consisting of C₁₋₄ alkyl,—(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl,halogen, —C(O)NR¹R², and —NR¹C(O)R²; C₃₋₇ carbocyclyl optionallysubstituted with 0-2 substituents selected from the group consisting ofC₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,—(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and —NR¹C(O)R²; 5-10membered heteroaryl optionally substituted with 0-2 substituentsselected from the group consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR¹,—(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen,—C(O)NR¹R², and —NR¹C(O)R²; and 3-10 membered heterocyclyl optionallysubstituted with 0-2 substituents selected from the group consisting ofC₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,—(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and —NR¹C(O)R².

In some embodiments of Formula (I′), (II′), (I), (II), (Ia), (Ib), (Ic),(Id), (IIa), (IIb), or (IIc), R⁵ is halogen. In some embodiments, R⁵ isF.

In some embodiments, R⁵ is —S—C₁-C₆alkyl, —S—C₁-C₆ cycloalkyl, or —S-4to 10 membered heterocyclyl. In some embodiments, R⁵ is —S—CH₃.

In some embodiments, R⁵ is —O—C₁-C₆alkyl, —O—C₁-C₆ cycloalkyl, or —O-4to 10 membered heterocyclyl. In some embodiments, R⁵ is

In some embodiments, R⁵ is —OCH₃.

In some embodiments of Formula (I′), (II′), (I), (Ia), (Ib), (Ic), (Id),(IIa), (IIb), or (IIc), n is 0 or 1; Y² is —NH—; G is selected from thegroup consisting of —C(O)R⁴, —C(O)(CH₂)₀₋₃SR³, —C(O)(CH₂)₁₋₃R⁴,—C(O)OR³, —C(O)NR¹R², —S(O)₂R³, —C(═NR¹)R⁴, and —C(═NR¹)NR¹R².

In some embodiments, G is selected from the group consisting of —C(O)R⁴,—C(O)(CH₂)₀₋₃SR³, —C(O)OR³, —C(O)NR¹R², —S(O)₂R³, —C(═NR¹)R⁴, and—C(═NR¹)NR¹R². In some embodiments, G is —C(O)R⁴. In some embodiments, Gis —C(O)(CH₂)R⁴.

In some embodiments of Formula (I), (Ia), (Ib), (Ic), (Id), (IIa),(IIb), or (IIc), G is —C(O)R⁴; wherein R⁴ is optionally substitutedC₁₋₄alkyl or R⁴ is C₁₋₄alkyl substituted with C₁-C₄ alkylthio or R⁴ isC₁₋₄alkyl substituted with 5-10 membered heteroaryl optionallysubstituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, andC₁-C₆ haloalkoxy or R⁴ is optionally substituted 5-10 memberedheteroaryl or R⁴ is 5-10 membered heteroaryl substituted with amino. Insome embodiments, for the R⁴ in G, R⁴ is optionally substitutedC₁₋₄alkyl. R⁴ is C₁₋₄alkyl substituted with C₁-C₄ alkylthio. In someembodiments, for the R⁴ in G, R⁴ is —CH₂SCH₃. In some embodiments, forthe R⁴ in G, R⁴ is C₁₋₄alkyl substituted with 5-10 membered heteroaryloptionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, and C₁-C₆ haloalkoxy. In some embodiments, for the R⁴ in G,R⁴ is

In some embodiments, for the R⁴ in G, R⁴ is optionally substituted 5-10membered heteroaryl. In some embodiments, for the R⁴ in G, R⁴ is 5-10membered heteroaryl substituted with amino. In some embodiments, R⁴

In some embodiments, G is

In some embodiments, G is

In some embodiments, G is optionally substituted C₆₋₁₀aryl. In someembodiments, G is —S(O)(CH₂)₁₋₃R³, —S(O)₂NR¹R², —S(O)₂NR¹OR³,—NR¹S(O)₂NR¹OR³, —CN, —OR¹, —SR¹, or —NR¹R².

In some embodiments of Formula (I′), (II′), (I), (Ia), (Ib), (Ic), (Id),(IIa), (IIb), or (IIc), G is —C(O)CH₂SR³.

In some embodiments of Formula (I′), (II′), (I), (Ia), (Ib), (Ic), (Id),(IIa), (IIb), or (IIc), when G is —C(O)CH₂SR³, R³ is C₁₋₄alkyl. In someembodiments, G is —C(O)(CH₂)SCH₃.

In some embodiments of Formula (I′), (II′), (I), (Ia), (Ib), (Ic), (Id),(IIa), (IIb), or (IIc), when G is —C(O)CH₂SR³, R³ is 5-10 memberedheterocyclyl.

In some embodiments of Formula (I′), (II′), (I), (Ia), (Ib), (Ic), (Id),(IIa), (IIb), or (IIc), Y² is —S(O)₂—.

In some embodiments of Formula (I′), (II′), (I), (Ia), (Ib), (Ic), (Id),(IIa), (IIb), or (IIc), wherein Y² is —S(O)₂—, G is optionallysubstituted C₆₋₁₀aryl.

In some embodiments of Formula (I′), (II′), (I), (Ia), (Ib), (Ic), (Id),(IIa), (IIb), or (IIc), Y¹ is CH or N. In some embodiments, Y¹ is CH. Insome embodiments, Y¹ is N.

Some embodiments include a compound selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.

Some embodiments of the compounds of Formula (III′) or (III) can havethe structure of Formula (IIIa):

-   -   or its pharmaceutically acceptable salts

Some embodiments of the compounds of Formula (III′) or (III) can havethe structure of Formula (IIIb):

-   -   or its pharmaceutically acceptable salts.

Some embodiments of the compounds of Formula (III′) or (III) can havethe structure of Formula (IIIc):

-   -   or its pharmaceutically acceptable salts, wherein:    -   m is 0, 1, or 2; and    -   J, L, and M are each independently selected from the group        consisting of CR⁵ and N.

Some embodiments of the compounds of Formula (III′), (III), or (IIIc)can have the structure of Formula (IIId):

-   -   or its pharmaceutically acceptable salts.

Some embodiments of the compounds of Formula (IV′) or (IV) can have thestructure of Formula (IVa):

-   -   or its pharmaceutically acceptable salts, wherein:    -   m is 0, 1, or 2; and    -   J, L, and M are each independently selected from the group        consisting of CR⁵ and N.

Some embodiments of the compounds of Formula (IV′), (IV), or (IVa) canhave the structure of Formula (IVb):

-   -   or its pharmaceutically acceptable salts.

Some embodiments of the compounds of Formula (III′), (IV′), (III) or(IV) can have the structure of Formula (III-1) or (IV-1):

-   -   wherein J, L, and M are each independently selected from the        group consisting of CR⁵ and N.

In some embodiments, for the compounds of Formula (III′) or (IV′), n¹ is1 and Q¹ and Q² are deuterium. In some embodiments, Q¹ is hydrogen andQ² is deuterium.

In some embodiments, for the compounds of Formula (III′), (IV′), (III),(IV), (III-1), or (IV-1), Y⁷ is CH₂, O, or S. In some embodiments, Y⁷ isCH₂. In some embodiments, Y⁷ is O. In some embodiments, Y⁷ is S. In someembodiments, Y⁷ is NH. In some embodiments, Y⁷ is O, n¹ is 1, and m is1.

Some embodiments of the compounds of Formula (III′), (IV′), (III), (IV),(III-1), (IV-1), or their pharmaceutically acceptable salts can have thestructure of Formula (III-2), or (IV-2):

In some embodiments, M is CR⁵. In some embodiments, M is N. In someembodiments, M is CH. In some embodiments, J is N, and L and M are eachindependently CR⁵. In some embodiments, L is N, and J and M are eachindependently CR⁵. In some embodiments, M is N, and J and L are eachindependently CR⁵.

In some embodiments, J and L are each independently CR⁵. In someembodiments, J and L are CH. In some embodiments, MJ and M are CH. Insome embodiments, L and M are CH.

In some embodiments, R⁵ is selected from the group consisting ofC₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ carbocyclyl, C₁-C₆heteroalkyl, 5-10 membered heterocyclyl, C₆-C₁₀ aryl, 5-10 memberedheteroaryl, cyano, hydroxy, —OR³, —SR³, —S(O)₂M′, —P(O)R¹M′, andhalogen. In some embodiments, R⁵ is halogen. In some embodiments, R⁵ isF. In some embodiments, R⁵ is alkoxy. In some embodiments, R⁵ is —OCH₃.In some embodiments, R⁵ is —OCH₂CH₃. In some embodiments, R⁵ is —OH. Insome embodiments, R⁵ is —SH. In some embodiments, R⁵ is —SCH₃. In someembodiments, R⁵ is —S(O)₂M′. In some embodiments, R⁵ is —S(O)₂CH₃. Insome embodiments, R⁵ is —SOM′. In some embodiments, R⁵ is —S(O)₂CH₃. Insome embodiments, R⁵ is cyano. In some embodiments, R⁵ is —C≡CH. In someembodiments, R⁵ is —CHF₂. In some embodiments, R⁵ is —CF₃. In someembodiments, R⁵ is —C(O)NR¹R². In some embodiments, R⁵ is —C(O)NH₂. Insome embodiments, R⁵ is —C(═NR¹)R². In some embodiments, R⁵ is—CH═N—OCH₃. In some embodiments, R⁵ is —COOR¹. In some embodiments, R⁵is —COOH. In some embodiments, R⁵ is a C₂₋₄ alkynyl, triazole, ordiazole, optionally substituted with 0-2 substituents selected from—(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl,halogen, —C(O)NR¹R², and —NR¹C(O)R². In some embodiments, R⁵ is

In some embodiments, R⁵ is —(CH₂)_(p)—Y³—(CH₂)_(q)M′.

In some embodiments, Y³ is —S—, —O—, or —NH—. In some embodiments, Y³ is—S—. In some embodiments, Y³ is —O—. In some embodiments, Y³ is —NH—. Insome embodiments, Y³ is —S(O)— or —S(O)₂—. In some embodiments, Y³ is—S(O)—. In some embodiments, Y³ is —S(O)₂—.

In some embodiments, M′ is a 5-10 membered heteroaryl or 3-10 memberedheterocyclyl, each optionally substituted with 0-2 substituents selectedfrom the group consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN,—(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and—NR¹C(O)R². In some embodiments, M′ is azetine, thiadiazole, triazole,dioxolane, pyridine, morpholine, or cyclopropyl, each optionallysubstituted with 0-2 substituents selected from the group consisting ofC₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,—(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and —NR¹C(O)R². In someembodiments, M′ is

each optionally substituted with 0-2 substituents selected from thegroup consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN,—(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and—NR¹C(O)R². In some embodiments, M′ is

In some embodiments, M′ is cyano. In some embodiments, M′ is —OH. Insome embodiments, M′ is —S(O)₂R¹ or —S(O)₂NR¹R². In some embodiments, M′is —S(O)₂CH₃ or —S(O)₂NH₂. In some embodiments, M′ is —C(O)NR¹R². Insome embodiments, M′ is —C(O)NH₂. In some embodiments, M′ is C₁₋₄ alkyloptionally substituted with 0-2 substituents selected from the groupconsisting of —OR¹, —CN, —NR¹R², -heterocyclyl halogen, —C(O)NR¹R², and—NR¹C(O)R²; C₂₋₄ alkenyl optionally substituted with 0-2 substituentsselected from the group consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR¹,—(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen,—C(O)NR¹R², and —NR¹C(O)R²; or C₂₋₄ alkynyl optionally substituted with0-2 substituents selected from the group consisting of C₁₋₄ alkyl,—(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl,halogen, —C(O)NR¹R², and —NR¹C(O)R². In some embodiments, M′ is —C≡CH.In some embodiments, M′ is —C≡C—(CH₂)₀₋₄OR¹, —C≡C—(CH₂)₀₋₄NR¹R², or—C≡C—(CH₂)₀₋₄-heterocyclyl. In some embodiments, M′ is —C≡C—(CH₂)—OCH₃,—C≡C—(CH₂)—OH, —C≡C—(CH₂)—NH₂, or

In some embodiments, M′ is —(CH₂)₃NH₂, CH₂F, CHF₂, CF₃, CH(CH₂OH)₂, orCH₂N(CH₃)₂. In some embodiments, M′ is C₁₋₄ alkyl.

In some embodiments, R⁵ is present twice. In some embodiments,

L and M are each independently CR⁵; J is CH; and each R⁵ isindependently selected from the group consisting of OH, halogen, CN,—C(O)OR¹; —C(O)NR¹R²; —C(O)NR¹OR²; —NR¹C(O)R²; —NR¹C(O)NR²R³;—NR¹C(O)OR²; —NR¹S(O)₂R²; —NR¹S(O)₂NR²R³; —C(═NR¹)R²; —C(═NR¹)NR²R³;—NR¹CR² (═NR³); —NR¹C(═NR²)NR³R⁴; —S(O)(CH₂)₁₋₃R⁴, —S(O)₂NR¹R²,—S(O)₂NR¹OR³, —NR¹S(O)₂NR¹OR³, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₇ carbocyclyl, optionallysubstituted 5-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, cyano, C₁-C₆alkoxy(C₁-C₆)alkyl, aryloxy, sulfhydryl (mercapto), and—(CH₂)_(p)—Y³—(CH₂)_(q)M′. In some embodiments, each R⁵ is independentlyhalogen or —OM′. In some embodiments, each R⁵ is independently F or—OCH₃. In some embodiments, each R⁵ is independently Cl or —OCH₃.

In some embodiments, R⁶ is —COOR or —P(O)(OR)₂. In some embodiments, R¹is —COOH or —P(O)(OH)₂.

In some embodiments, R is H. In some embodiments, R is alkali metal orNH₄ ⁺. In some embodiments, R is Na.

Some specific embodiments of the compounds described herein have thestructure selected from the group consisting of

and pharmaceutically acceptable salts thereof.

Some specific embodiments of the compounds described herein have thestructure selected from the group consisting of

and pharmaceutically acceptable salts thereof.

In some embodiments, the pharmaceutically acceptable salt is an alkalinemetal salt or ammonium salt. In some embodiments, the pharmaceuticallyacceptable salt is a sodium salt.

In some embodiments, the compound of formula (III) or (IV) can have thestructure selected from

In some embodiments, the compound of formula (III′), (III), (IV) and(IV′) can have the structure selected from

Where the compounds disclosed herein have at least one chiral center,they may exist as individual enantiomers and diastereomers or asmixtures of such isomers, including racemates. Separation of theindividual isomers or selective synthesis of the individual isomers isaccomplished by application of various methods which are well known topractitioners in the art. Unless otherwise indicated, all such isomersand mixtures thereof are included in the scope of the compoundsdisclosed herein. Furthermore, compounds disclosed herein may exist inone or more crystalline or amorphous forms. Unless otherwise indicated,all such forms are included in the scope of the compounds disclosedherein including any polymorphic forms. In addition, some of thecompounds disclosed herein may form solvates with water (i.e., hydrates)or common organic solvents. Unless otherwise indicated, such solvatesare included in the scope of the compounds disclosed herein.

The skilled artisan will recognize that some structures described hereinmay be resonance forms or tautomers of compounds that may be fairlyrepresented by other chemical structures, even when kinetically; theartisan recognizes that such structures may only represent a very smallportion of a sample of such compound(s). Such compounds are consideredwithin the scope of the structures depicted, though such resonance formsor tautomers are not represented herein.

Isotopes may be present in the compounds described. Each chemicalelement as represented in a compound structure may include any isotopeof said element. For example, in a compound structure a hydrogen atommay be explicitly disclosed or understood to be present in the compound.At any position of the compound that a hydrogen atom may be present, thehydrogen atom can be any isotope of hydrogen, including but not limitedto hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, referenceherein to a compound encompasses all potential isotopic forms unless thecontext clearly dictates otherwise.

In some embodiments, due to the facile exchange of boron esters, thecompounds described herein may convert to or exist in equilibrium withalternate forms. Accordingly, in some embodiments, the compoundsdescribed herein may exist in combination with one or more of theseforms. For example, as shown below, the compounds disclosed herein mayexist in cyclic boronate monoesters as formula I′ or in acyclic form asboronic acids as formula II′, or may exist as a mixture of the two formsdepending on the medium; the compounds disclosed herein may exist incyclic form as cyclic boronate monoesters as formula III-1 or in acyclicform as boronic acids as formula IV-1, or may exist as a mixture of thetwo forms depending on the medium; the compounds disclosed herein mayexist in cyclic boronate monoesters as formula I or in acyclic form asboronic acids as formula II, or may exist as a mixture of the two formsdepending on the medium. In another example, the compounds disclosedherein may exist in cyclic form as cyclic boronate monoesters as formulaIII′ or in acyclic form as boronic acids as formula IV′, or may exist asa mixture of the two forms depending on the medium; the compoundsdisclosed herein may exist in cyclic form as cyclic boronate monoestersas formula III-1 or in acyclic form as boronic acids as formula IV-1, ormay exist as a mixture of the two forms depending on the medium.

In some embodiments, the compounds described herein may exist in cyclicdimeric form as Formula (C) or trimeric form as Formula (D), tetramericform as Formula (E) as shown below, or acylic dimeric, trimeric ortetrameric forms and the like. In some embodiments, Q can be H or—Y²—(CH₂)_(n)-G; Y′ can be CR¹ or N; and X′ can be —Y²—(CH₂)_(n)-G inFormula C, D and E.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this disclosure belongs. All patents, applications,published applications, and other publications are incorporated byreference in their entirety. In the event that there is a plurality ofdefinitions for a term herein, those in this section prevail unlessstated otherwise.

A “prodrug” refers to an agent that is converted into the parent drug invivo. Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. An example, without limitation, of a prodrug wouldbe a compound which is administered as an ester (the “prodrug”) tofacilitate transmittal across a cell membrane where water solubility isdetrimental to mobility but which then is metabolically hydrolyzed tothe carboxylic acid, the active entity, once inside the cell wherewater-solubility is beneficial. A further example of a prodrug might bea short peptide (polyaminoacid) bonded to an acid group where thepeptide is metabolized to reveal the active moiety. Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in Design of Prodrugs, (ed. H.Bundgaard, Elsevier, 1985), which is hereby incorporated herein byreference in its entirety.

The term “pro-drug ester” refers to derivatives of the compoundsdisclosed herein formed by the addition of any of several ester-forminggroups that are hydrolyzed under physiological conditions. Examples ofpro-drug ester groups include pivoyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, as well as other such groupsknown in the art, including a (5-R-2-oxo-1,3-dioxolen-4-yl)methyl group.Other examples of pro-drug ester groups can be found in, for example, T.Higuchi and V. Stella, in “Pro-drugs as Novel Delivery Systems”, Vol.14, A.C.S. Symposium Series, American Chemical Society (1975); and“Bioreversible Carriers in Drug Design: Theory and Application”, editedby E. B. Roche, Pergamon Press: New York, 14-21 (1987) (providingexamples of esters useful as prodrugs for compounds containing carboxylgroups). Each of the above-mentioned references is herein incorporatedby reference in their entirety.

“Metabolites” of the compounds disclosed herein include active speciesthat are produced upon introduction of the compounds into the biologicalmilieu.

“Solvate” refers to the compound formed by the interaction of a solventand a compound described herein, a metabolite, or salt thereof. Suitablesolvates are pharmaceutically acceptable solvates including hydrates.

The term “pharmaceutically acceptable salt” refers to salts that retainthe biological effectiveness and properties of a compound, which are notbiologically or otherwise undesirable for use in a pharmaceutical. Inmany cases, the compounds herein are capable of forming acid and/or basesalts by virtue of the presence of amino and/or carboxyl groups orgroups similar thereto. Pharmaceutically acceptable acid addition saltscan be formed with inorganic acids and organic acids. Inorganic acidsfrom which salts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like; particularly preferred are the ammonium,potassium, sodium, calcium and magnesium salts. Organic bases from whichsalts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike, specifically such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, and ethanolamine. Many such salts areknown in the art, as described in WO 87/05297, Johnston et al.,published Sep. 11, 1987 (incorporated by reference herein in itsentirety). Some examples of pharmaceutically acceptable base additionsalts of the compounds disclosed herein have the structure of Formula(IIIc-salt) or (IVa-salt):

wherein Z can be an alkali metal or NH₄ ⁺; and R can be an alkali metalor NH₄ ⁺. Some additional examples of pharmaceutically acceptable baseaddition salts of the compounds described herein have the structure ofFormula (IIId-salt) or (Ivb-salt):

Some other examples of pharmaceutically acceptable base addition saltsof the compounds described herein have the structure of Formula (I-salt)or (II-salt):

As used herein, “C_(a) to C_(b)” or “C_(a-b)” in which “a” and “b” areintegers refer to the number of carbon atoms in the specified group.That is, the group can contain from “a” to “b”, inclusive, carbon atoms.Thus, for example, a “C₁ to C₄ alkyl” or “C₁₋₄ alkyl” group refers toall alkyl groups having from 1 to 4 carbons, that is, CH₃—, CH₃CH₂—,CH₃CH₂CH₂—, (CH₃)₂CH—, CH₃CH₂CH₂CH₂—, CH₃CH₂CH(CH₃)— and (CH₃)₃C—.

The term “halogen” or “halo,” as used herein, means any one of theradio-stable atoms of column 7 of the Periodic Table of the Elements,e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorinebeing preferred.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that is fully saturated (i.e., contains no double or triplebonds). The alkyl group may have 1 to 20 carbon atoms (whenever itappears herein, a numerical range such as “1 to 20” refers to eachinteger in the given range; e.g., “1 to 20 carbon atoms” means that thealkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbonatoms, etc., up to and including 20 carbon atoms, although the presentdefinition also covers the occurrence of the term “alkyl” where nonumerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 9 carbon atoms. The alkyl group could also be alower alkyl having 1 to 4 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁₋₄ alkyl” or similar designations. By way ofexample only, “C₁₋₄ alkyl” indicates that there are one to four carbonatoms in the alkyl chain, i.e., the alkyl chain is selected from thegroup consisting of methyl, ethyl, propyl, iso-propyl, n-butyl,iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but arein no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tertiary butyl, pentyl, hexyl, and the like.

As used herein, “alkoxy” refers to the formula —OR wherein R is an alkylas is defined above, such as “C₁₋₉ alkoxy”, including but not limited tomethoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,iso-butoxy, sec-butoxy, and tert-butoxy, and the like.

As used herein, “alkylthio” refers to the formula —SR wherein R is analkyl as is defined above, such as “C₁₋₉ alkylthio” and the like,including but not limited to methylmercapto, ethylmercapto,n-propylmercapto, 1-methylethylmercapto (isopropylmercapto),n-butylmercapto, iso-butylmercapto, sec-butylmercapto,tert-butylmercapto, and the like.

As used herein, “alkenyl” refers to a straight or branched hydrocarbonchain containing one or more double bonds. The alkenyl group may have 2to 20 carbon atoms, although the present definition also covers theoccurrence of the term “alkenyl” where no numerical range is designated.The alkenyl group may also be a medium size alkenyl having 2 to 9 carbonatoms. The alkenyl group could also be a lower alkenyl having 2 to 4carbon atoms. The alkenyl group of the compounds may be designated as“C₂₋₄ alkenyl” or similar designations. By way of example only, “C₂₋₄alkenyl” indicates that there are two to four carbon atoms in thealkenyl chain, i.e., the alkenyl chain is selected from the groupconsisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl,buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl,2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl,buta-1,3-dienyl, buta-1,2,-dienyl, and buta-1,2-dien-4-yl. Typicalalkenyl groups include, but are in no way limited to, ethenyl, propenyl,butenyl, pentenyl, and hexenyl, and the like.

As used herein, “alkynyl” refers to a straight or branched hydrocarbonchain containing one or more triple bonds. The alkynyl group may have 2to 20 carbon atoms, although the present definition also covers theoccurrence of the term “alkynyl” where no numerical range is designated.The alkynyl group may also be a medium size alkynyl having 2 to 9 carbonatoms. The alkynyl group could also be a lower alkynyl having 2 to 4carbon atoms. The alkynyl group of the compounds may be designated as“C₂₋₄ alkynyl” or similar designations. By way of example only, “C₂₋₄alkynyl” indicates that there are two to four carbon atoms in thealkynyl chain, i.e., the alkynyl chain is selected from the groupconsisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl,butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are in noway limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, andthe like.

As used herein, “heteroalkyl” refers to a straight or branchedhydrocarbon chain containing one or more heteroatoms, that is, anelement other than carbon, including but not limited to, nitrogen,oxygen and sulfur, in the chain backbone. The heteroalkyl group may have1 to 20 carbon atoms although the present definition also covers theoccurrence of the term “heteroalkyl” where no numerical range isdesignated. The heteroalkyl group may also be a medium size heteroalkylhaving 1 to 9 carbon atoms. The heteroalkyl group could also be a lowerheteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group of thecompounds may be designated as “C₁₋₄ heteroalkyl” or similardesignations. The heteroalkyl group may contain one or more heteroatoms.By way of example only, “C₁₋₄ heteroalkyl” indicates that there are oneto four carbon atoms in the heteroalkyl chain and additionally one ormore heteroatoms in the backbone of the chain.

The term “aromatic” refers to a ring or ring system having a conjugatedpi electron system and includes both carbocyclic aromatic (e.g., phenyl)and heterocyclic aromatic groups (e.g., pyridine). The term includesmonocyclic or fused-ring polycyclic (i.e., rings which share adjacentpairs of atoms) groups provided that the entire ring system is aromatic.

As used herein, “aryl” refers to an aromatic ring or ring system (i.e.,two or more fused rings that share two adjacent carbon atoms) containingonly carbon in the ring backbone. When the aryl is a ring system, everyring in the system is aromatic. The aryl group may have 6 to 18 carbonatoms, although the present definition also covers the occurrence of theterm “aryl” where no numerical range is designated. In some embodiments,the aryl group has 6 to 10 carbon atoms. The aryl group may bedesignated as “C₆₋₁₀ aryl,” “C₆ or C₁₀ aryl,” or similar designations.Examples of aryl groups include, but are not limited to, phenyl,naphthyl, azulenyl, and anthracenyl.

As used herein, “aryloxy” and “arylthio” refers to RO— and RS—, in whichR is an aryl as is defined above, such as “C₆₋₁₀ aryloxy” or “C₆₋₁₀arylthio” and the like, includingbut not limited to phenyloxy.

An “aralkyl” or “arylalkyl” is an aryl group connected, as asubstituent, via an alkylene group, such “C₇₋₁₄ aralkyl” and the like,including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl, andnaphthylalkyl. In some cases, the alkylene group is a lower alkylenegroup (i.e., a C₁₋₄ alkylene group).

As used herein, “heteroaryl” refers to an aromatic ring or ring system(i.e., two or more fused rings that share two adjacent atoms) thatcontain(s) one or more heteroatoms, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen and sulfur, inthe ring backbone. When the heteroaryl is a ring system, every ring inthe system is aromatic. The heteroaryl group may have 5-18 ring members(i.e., the number of atoms making up the ring backbone, including carbonatoms and heteroatoms), although the present definition also covers theoccurrence of the term “heteroaryl” where no numerical range isdesignated. In some embodiments, the heteroaryl group has 5 to 10 ringmembers or 5 to 7 ring members. The heteroaryl group may be designatedas “5-7 membered heteroaryl,” “5-10 membered heteroaryl,” or similardesignations. Examples of heteroaryl rings include, but are not limitedto, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,indolyl, isoindolyl, and benzothienyl.

A “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, asa substituent, via an alkylene group. Examples include but are notlimited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl,pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. Insome cases, the alkylene group is a lower alkylene group (i.e., a C₁₋₄alkylene group).

As used herein, “carbocyclyl” means a non-aromatic cyclic ring or ringsystem containing only carbon atoms in the ring system backbone. Whenthe carbocyclyl is a ring system, two or more rings may be joinedtogether in a fused, bridged or spiro-connected fashion. Carbocyclylsmay have any degree of saturation provided that at least one ring in aring system is not aromatic. Thus, carbocyclyls include cycloalkyls,cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20carbon atoms, although the present definition also covers the occurrenceof the term “carbocyclyl” where no numerical range is designated. Thecarbocyclyl group may also be a medium size carbocyclyl having 3 to 10carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3to 6 carbon atoms. The carbocyclyl group may be designated as “C₃₋₆carbocyclyl” or similar designations. Examples of carbocyclyl ringsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl,adamantyl, and spiro[4.4]nonanyl.

A “(carbocyclyl)alkyl” is a carbocyclyl group connected, as asubstituent, via an alkylene group, such as “C₄₋₁₀ (carbocyclyl)alkyl”and the like, including but not limited to, cyclopropylmethyl,cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl,cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl,cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. Insome cases, the alkylene group is a lower alkylene group.

As used herein, “cycloalkyl” means a fully saturated carbocyclyl ring orring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

As used herein, “cycloalkenyl” means a carbocyclyl ring or ring systemhaving at least one double bond, wherein no ring in the ring system isaromatic. An example is cyclohexenyl.

As used herein, “heterocyclyl” means a non-aromatic cyclic ring or ringsystem containing at least one heteroatom in the ring backbone.Heterocyclyls may be joined together in a fused, bridged orspiro-connected fashion. Heterocyclyls may have any degree of saturationprovided that at least one ring in the ring system is not aromatic. Theheteroatom(s) may be present in either a non-aromatic or aromatic ringin the ring system. The heterocyclyl group may have 3 to 20 ring members(i.e., the number of atoms making up the ring backbone, including carbonatoms and heteroatoms), although the present definition also covers theoccurrence of the term “heterocyclyl” where no numerical range isdesignated. The heterocyclyl group may also be a medium sizeheterocyclyl having 3 to 10 ring members. The heterocyclyl group couldalso be a heterocyclyl having 3 to 6 ring members. The heterocyclylgroup may be designated as “3-6 membered heterocyclyl” or similardesignations. In preferred six membered monocyclic heterocyclyls, theheteroatom(s) are selected from one up to three of O, N or S, and inpreferred five membered monocyclic heterocyclyls, the heteroatom(s) areselected from one or two heteroatoms selected from O, N, or S. Examplesof heterocyclyl rings include, but are not limited to, azepinyl,acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl,imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl,piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl,pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl,1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl,1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl,hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl,1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl,oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl,isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl,thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, andtetrahydroquinoline.

A “(heterocyclyl)alkyl” is a heterocyclyl group connected, as asubstituent, via an alkylene group. Examples include, but are notlimited to, imidazolinylmethyl and indolinylethyl.

As used herein, “acyl” refers to —C(═O)R, wherein R is hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein.Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, andacryl.

An “O-carboxy” group refers to a “—OC(═O)R” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein.

A “C-carboxy” group refers to a “—C(═O)OR” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein. A non-limiting example includes carboxyl (i.e.,—C(═O)OH).

A “cyano” group refers to a “—CN” group.

A “cyanato” group refers to an “—OCN” group.

An “isocyanato” group refers to a “—NCO” group.

A “thiocyanato” group refers to a “—SCN” group.

An “isothiocyanato” group refers to an “—NCS” group.

A “sulfinyl” group refers to an “—S(═O)R” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein.

A “sulfonyl” group refers to an “—SO₂R” group in which R is selectedfrom hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, asdefined herein.

An “S-sulfonamido” group refers to a “—SO₂NR_(A)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “N-sulfonamido” group refers to a “—N(R_(A))SO₂R_(B)” group in whichR_(A) and R_(b) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “O-carbamyl” group refers to a “—OC(═O)NR_(A)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “N-carbamyl” group refers to an “—N(R_(A))OC(═O)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “O-thiocarbamyl” group refers to a “—OC(═S)NR_(A)R_(B)” group inwhich R_(A) and R_(B) are each independently selected from hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, aC₆₋₁₀ ryl,5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as definedherein.

An “N-thiocarbamyl” group refers to an “—N(R_(A))OC(═S)R_(B)” group inwhich R_(A) and R_(B) are each independently selected from hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as definedherein.

A “C-amido” group refers to a “—C(═O)NR_(A)R_(B)” group in which R_(A)and R_(B) are each independently selected from hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “N-amido” group refers to a “—N(R_(A))C(═O)R_(B)” group in whichR_(A) and R_(B) are each independently selected from hydrogen, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “amino” group refers to a “—NR_(A)R_(B)” group in which R_(A) andR_(B) are each independently selected from hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 5-10 membered heterocyclyl, as defined herein.

An “aminoalkyl” group refers to an amino group connected via an alkylenegroup.

An “alkoxyalkyl” group refers to an alkoxy group connected via analkylene group, such as a “C₂₋₈ alkoxyalkyl” and the like.

As used herein, a substituted group is derived from the unsubstitutedparent group in which there has been an exchange of one or more hydrogenatoms for another atom or group. Unless otherwise indicated, when agroup is deemed to be “substituted,” it is meant that the group issubstituted with one or more substitutents independently selected fromC₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆ heteroalkyl, C₃-C₇carbocyclyl (optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy),C₃-C₇-carbocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10membered heterocyclyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 memberedheterocyclyl-C₁-C₆-alkyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), aryl (optionallysubstituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, andC₁-C₆ haloalkoxy), aryl(C₁-C₆)alkyl (optionally substituted with halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10membered heteroaryl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), 5-10 memberedheteroaryl(C₁-C₆)alkyl (optionally substituted with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy), halo, cyano,hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl (i.e., ether), aryloxy,sulfhydryl (mercapto), halo(C₁-C₆)alkyl (e.g., —CF₃), halo(C₁-C₆)alkoxy(e.g., —OCF₃), C₁-C₆ alkylthio, arylthio, amino, amino(C₁-C₆)alkyl,nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido,N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl,cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl,and oxo (═O). Wherever a group is described as “optionally substituted”that group can be substituted with the above substituents.

In some embodiments, substituted group(s) is (are) substituted with oneor more substituent(s) individually and independently selected fromC₁-C₄ alkyl, amino, hydroxy, and halogen.

It is to be understood that certain radical naming conventions caninclude either a mono-radical or a di-radical, depending on the context.For example, where a substituent requires two points of attachment tothe rest of the molecule, it is understood that the substituent is adi-radical. For example, a substituent identified as alkyl that requirestwo points of attachment includes di-radicals such as —CH₂—, —CH₂CH₂—,—CH₂CH(CH₃)CH₂—, and the like. Other radical naming conventions clearlyindicate that the radical is a di-radical such as “alkylene” or“alkenylene.”

As used herein, “alkylene” means a branched, or straight chain fullysaturated di-radical chemical group containing only carbon and hydrogenthat is attached to the rest of the molecule via two points ofattachment (i.e., an alkanediyl). The alkylene group may have 1 to 20carbon atoms, although the present definition also covers the occurrenceof the term alkylene where no numerical range is designated. Thealkylene group may also be a medium size alkylene having 1 to 9 carbonatoms. The alkylene group could also be a lower alkylene having 1 to 4carbon atoms. The alkylene group may be designated as “C₁₋₄ alkylene” orsimilar designations. By way of example only, “C₁₋₄ alkylene” indicatesthat there are one to four carbon atoms in the alkylene chain, i.e., thealkylene chain is selected from the group consisting of methylene,ethylene, ethan-1,1-diyl, propylene, propan-1,1-diyl, propan-2,2-diyl,1-methyl-ethylene, butylene, butan-1,1-diyl, butan-2,2-diyl,2-methyl-propan-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene,1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

As used herein, “alkenylene” means a straight or branched chaindi-radical chemical group containing only carbon and hydrogen andcontaining at least one carbon-carbon double bond that is attached tothe rest of the molecule via two points of attachment. The alkenylenegroup may have 2 to 20 carbon atoms, although the present definitionalso covers the occurrence of the term alkenylene where no numericalrange is designated. The alkenylene group may also be a medium sizealkenylene having 2 to 9 carbon atoms. The alkenylene group could alsobe a lower alkenylene having 2 to 4 carbon atoms. The alkenylene groupmay be designated as “C₂₋₄ alkenylene” or similar designations. By wayof example only, “C₂₋₄ alkenylene” indicates that there are two to fourcarbon atoms in the alkenylene chain, i.e., the alkenylene chain isselected from the group consisting of ethenylene, ethen-1,1-diyl,propenylene, propen-1,1-diyl, prop-2-en-1,1-diyl, 1-methyl-ethenylene,but-1-enylene, but-2-enylene, but-1,3-dienylene, buten-1,1-diyl,but-1,3-dien-1,1-diyl, but-2-en-1,1-diyl, but-3-en-1,1-diyl,1-methyl-prop-2-en-1,1-diyl, 2-methyl-prop-2-en-1,1-diyl,1-ethyl-ethenylene, 1,2-dimethyl-ethenylene, 1-methyl-propenylene,2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propen-1,1-diyl,and 2,2-dimethyl-ethen-1,1-diyl.

When two R groups are said to form a ring (e.g., a carbocyclyl,heterocyclyl, aryl, or heteroaryl ring) “together with the atom to whichthey are attached,” it is meant that the collective unit of the atom andthe two R groups are the recited ring. The ring is not otherwise limitedby the definition of each R group when taken individually. For example,when the following substructure is present:

and R¹ and R² are defined as selected from the group consisting ofhydrogen and alkyl, or R¹ and R² together with the nitrogen to whichthey are attached form a heteroaryl, it is meant that R¹ and R² can beselected from hydrogen or alkyl, or alternatively, the substructure hasstructure:

where ring A is a heteroaryl ring containing the depicted nitrogen.

Similarly, when two “adjacent” R groups are said to form a ring“together with the atoms to which they are attached,” it is meant thatthe collective unit of the atoms, intervening bonds, and the two Rgroups are the recited ring. For example, when the followingsubstructure is present:

and R¹ and R² are defined as selected from the group consisting ofhydrogen and alkyl, or R¹ and R² together with the atoms to which theyare attached form an aryl or carbocylyl, it is meant that R¹ and R² canbe selected from hydrogen or alkyl, or alternatively, the substructurehas structure:

where A is an aryl ring or a carbocylyl containing the depicted doublebond.

Wherever a substituent is depicted as a di-radical (i.e., has two pointsof attachment to the rest of the molecule), it is to be understood thatthe substituent can be attached in any directional configuration unlessotherwise indicated. Thus, for example, a substituent depicted as -AE-or

E includes the substituent being oriented such that the A is attached atthe leftmost attachment point of the molecule as well as the case inwhich A is attached at the rightmost attachment point of the molecule.

As used herein, “isosteres” of a chemical group are other chemicalgroups that exhibit the same or similar properties. For example,tetrazole is an isostere of carboxylic acid because it mimics theproperties of carboxylic acid even though they both have very differentmolecular formulae. Tetrazole is one of many possible isostericreplacements for carboxylic acid. Other carboxylic acid isosterescontemplated include —SO₃H, —SO₂HNR, —PO₂(R)₂, —PO₃(R)₂, —CONHNHSO₂R,—COHNSO₂R, and —CONRCN, where R is selected from hydrogen, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ carbocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 3-10 membered heterocyclyl, as defined herein. Inaddition, carboxylic acid isosteres can include 5-7 membered carbocyclesor heterocycles containing any combination of CH₂, O, S, or N in anychemically stable oxidation state, where any of the atoms of said ringstructure are optionally substituted in one or more positions. Thefollowing structures are non-limiting examples of carbocyclic andheterocyclic isosteres contemplated. The atoms of said ring structuremay be optionally substituted at one or more positions with R as definedabove.

It is also contemplated that when chemical substituents are added to acarboxylic isostere, the compound retains the properties of a carboxylicisostere. It is contemplated that when a carboxylic isostere isoptionally substituted with one or more moieties selected from R asdefined above, then the substitution and substitution position isselected such that it does not eliminate the carboxylic acid isostericproperties of the compound. Similarly, it is also contemplated that theplacement of one or more R substituents upon a carbocyclic orheterocyclic carboxylic acid isostere is not a substitution at one ormore atom(s) that maintain(s) or is/are integral to the carboxylic acidisosteric properties of the compound, if such substituent(s) woulddestroy the carboxylic acid isosteric properties of the compound.

Other carboxylic acid isosteres not specifically exemplified in thisspecification are also contemplated.

The term “agent” or “test agent” includes any substance, molecule,element, compound, entity, or a combination thereof. It includes, but isnot limited to, e.g., protein, polypeptide, peptide or mimetic, smallorganic molecule, polysaccharide, polynucleotide, and the like. It canbe a natural product, a synthetic compound, or a chemical compound, or acombination of two or more substances. Unless otherwise specified, theterms “agent”, “substance”, and “compound” are used interchangeablyherein.

The term “analog” is used herein to refer to a molecule thatstructurally resembles a reference molecule but which has been modifiedin a targeted and controlled manner, by replacing a specific substituentof the reference molecule with an alternate substituent. Compared to thereference molecule, an analog would be expected, by one skilled in theart, to exhibit the same, similar, or improved utility. Synthesis andscreening of analogs, to identify variants of known compounds havingimproved characteristics (such as higher binding affinity for a targetmolecule) is an approach that is well known in pharmaceutical chemistry.

The term “mammal” is used in its usual biological sense. Thus, itspecifically includes, but is not limited to, primates, includingsimians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep,goats, swine, rabbits, dogs, cats, rats and mice but also includes manyother species.

The term “microbial infection” refers to the invasion of the hostorganism, whether the organism is a vertebrate, invertebrate, fish,plant, bird, or mammal, by pathogenic microbes. This includes theexcessive growth of microbes that are normally present in or on the bodyof a mammal or other organism. More generally, a microbial infection canbe any situation in which the presence of a microbial population(s) isdamaging to a host mammal. Thus, a mammal is “suffering” from amicrobial infection when excessive numbers of a microbial population arepresent in or on a mammal's body, or when the effects of the presence ofa microbial population(s) is damaging the cells or other tissue of amammal. Specifically, this description applies to a bacterial infection.Note that the compounds of preferred embodiments are also useful intreating microbial growth or contamination of cell cultures or othermedia, or inanimate surfaces or objects, and nothing herein should limitthe preferred embodiments only to treatment of higher organisms, exceptwhen explicitly so specified in the claims.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions iscontemplated. In addition, various adjuvants such as are commonly usedin the art may be included. Considerations for the inclusion of variouscomponents in pharmaceutical compositions are described, e.g., in Gilmanet al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis ofTherapeutics, 8th Ed., Pergamon Press, which is incorporated herein byreference in its entirety.

“Subject” as used herein, means a human or a non-human mammal, e.g., adog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-humanprimate or a bird, e.g., a chicken, as well as any other vertebrate orinvertebrate.

An “effective amount” or a “therapeutically effective amount” as usedherein refers to an amount of a therapeutic agent that is effective torelieve, to some extent, or to reduce the likelihood of onset of, one ormore of the symptoms of a disease or condition, and includes curing adisease or condition. “Curing” means that the symptoms of a disease orcondition are eliminated; however, certain long-term or permanenteffects may exist even after a cure is obtained (such as extensivetissue damage).

“Treat,” “treatment,” or “treating,” as used herein refers toadministering a pharmaceutical composition for prophylactic and/ortherapeutic purposes. The term “prophylactic treatment” refers totreating a subject who does not yet exhibit symptoms of a disease orcondition, but who is susceptible to, or otherwise at risk of, aparticular disease or condition, whereby the treatment reduces thelikelihood that the patient will develop the disease or condition. Theterm “therapeutic treatment” refers to administering treatment to a

Methods of Preparation

The compounds disclosed herein may be synthesized by methods describedbelow, or by modification of these methods. Ways of modifying themethodology include, among others, temperature, solvent, reagents etc.,known to those skilled in the art. In general, during any of theprocesses for preparation of the compounds disclosed herein, it may benecessary and/or desirable to protect sensitive or reactive groups onany of the molecules concerned. This may be achieved by means ofconventional protecting groups, such as those described in ProtectiveGroups in Organic Chemistry (ed. J. F. W. McOmie, Plenum Press, 1973);and P. G. M. Green, T. W. Wutts, Protecting Groups in Organic Synthesis(3rd ed.) Wiley, New York (1999), which are both hereby incorporatedherein by reference in their entirety. The protecting groups may beremoved at a convenient subsequent stage using methods known from theart. Synthetic chemistry transformations useful in synthesizingapplicable compounds are known in the art and include e.g. thosedescribed in R. Larock, Comprehensive Organic Transformations, VCHPublishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons, 1995, which are both herebyincorporated herein by reference in their entirety. The routes shown anddescribed herein are illustrative only and are not intended, nor arethey to be construed, to limit the scope of the claims in any mannerwhatsoever. Those skilled in the art will be able to recognizemodifications of the disclosed syntheses and to devise alternate routesbased on the disclosures herein; all such modifications and alternateroutes are within the scope of the claims.

In the following schemes, protecting groups for oxygen atoms areselected for their compatibility with the requisite synthetic steps aswell as compatibility of the introduction and deprotection steps withthe overall synthetic schemes (P. G. M. Green, T. W. Wutts, ProtectingGroups in Organic Synthesis (3rd ed.) Wiley, New York (1999)). Handlingof protecting and/or sterodirecting groups specific to boronic acidderivatives is described in a recent review of chemistry of boronicacids: D. G. Hall (Ed.), Boronic Acids. Preparation and Application inOrganic Synthesis and Medicine, Wiley VCH (2005) and in earlier reviews:Matteson, D. S. (1988). Asymmetric synthesis with boronic esters.Accounts of Chemical Research, 21(8), 294-300, and Matteson, D. S.(1989). Tetrahedron, 45(7), 1859-1885), all of which are incorporatedherein by reference in their entirety. The latter review articles alsodescribe methodology for stereoselective insertion of halomethinefunctionality next to the boronate which is employed in the syntheticschemes below.

In addition to standard acid catalyzed deprotection, special methods forremoval of boronic acid protecting and/or sterodirecting groups methodsusing fluorides (Yuen, A. K. L., & Hutton, C. A. (2005). TetrahedronLetters, 46(46), 7899-7903—incorporated herein by reference in itsentirety) or periodate oxidation (Coutts, S. J., et al. (1994).Tetrahedron Letters, 35(29), 5109-5112—incorporated herein by referencein its entirety) can also be employed in preparations of the compoundsdisclosed herein.

In strategies employing pinanediol or other diol-based chiralauxiliaries for stereospecific introduction of new chiral centers, theearly stages of chemistry on boronic intermediates can be performed onchiral boronate esters or alternatively nonchiral borate/boronateintermediates can be used in early stages followed bytransesterification with chiral diols prior to the step wherestereoselection is required.

Synthesis of Compounds of Formula I′, I, III′ and III

The following example schemes are provided for the guidance of thereader, and collectively represent an example method for making thecompounds encompassed herein. Furthermore, other methods for preparingcompounds described herein will be readily apparent to the person ofordinary skill in the art in light of the following reaction schemes andexamples. Unless otherwise indicated, all variables are as definedabove.

Compounds of formula Ib where R is H can be prepared as depicted inschemes 1-4 from key intermediates VI, VIII and XII, which may beassembled by known reactions (Boronic Acids: Preparations andApplications in Organic Synthesis, Medicine and Materials, D. G. Hall,ed., Wiley-VCH, Weinheim, 2011, which is incorporated herein byreference in its entirety).

Compounds of formula Ib can be made starting from protected aryl orheteroaryl intermediates of formula B′ via a double Mattesonhomologation sequence (J. Org. Chem., 2013, 78, 10009-10023, which isincorporated herein by reference in its entirety). The compounds offormula B′ may be attained from A′ by means of several earlier knownmethods (WO00458679, which is incorporated herein by reference in itsentirety) with conventional protecting groups for R′ and R″, such asthose described in Protective Groups in Organic Chemistry (ed. J. F. W.McOmie, Plenum, 1973, which is incorporated herein by reference in itsentirety); and Protecting Groups in Organic Synthesis P. G. M. Wutts, T.W. Green, Wiley, New York, 1999, which is incorporated herein byreference in its entirety) from commercially available salicylic acidderivatives. Aryl compounds of formula A′ upon boronation by well-knownavailable methods (Chem. Rev. 2010, 110, 890-931, which is incorporatedherein by reference in its entirety) and boronate ester formation withdesired chiral auxiliary give precursor for Matteson homologation.Compounds of formula C′ where X═Cl and R′ is Boc and R″ is t-Butyl or R′and R″ are protected together as isopropylidine or any other groupsprotected separately or together in cyclic form may be made fromcompounds of formula B′ via homologation upon chloromethylene insertionwith good stereocontrol by Matteson reaction conditions (WO00946098,which is incorporated herein by reference in its entirety). Compounds offormula C′ where X is bromo may be made analogously to the chlorocompounds of Scheme 1, utilizing dibromomethane (J. Am. Chem. Soc. 1990,112, 3964-969, which is incorporated herein by reference in itsentirety). The halo derivatives of formula C′ where X is Cl or Brundergo stereospecific substitution to form thioethers (WO 04064755,which is incorporated herein by reference in its entirety), ethers (WO12067664, which is incorporated herein by reference in its entirety),amines (J. Organomet. Chem. 1979, 170, 259-64, which is incorporatedherein by reference in its entirety) or acetates (Tetrahedron 2005, 61,4427-4536, which is incorporated herein by reference in its entirety),to give compounds of formula V. In an alternate approach, compounds offormula C′ where Y² is S can be made via a thiol intermediate byalkylation or arylation to introduce various G groups. Such compoundsmay also be made via alkyl or thiomethylene boronate esters by reactionwith substituted benzyl halides (U.S. Pat. No. 6,586,615, which isincorporated herein by reference in its entirety). The resultingproducts of formula V where Y² is S or O can be further homologated by amethylene insertion in a second Matteson reaction to give compounds offormula VI. Additionally, halo derivatives of formula C′ where X is Clor Br undergo stereospecific substitution to form azides which can befurther elaborated to compounds of formula VI where Y²═—NR2- byhomologation, reduction, alkylation or amide formation sequence (WO01002424, which is incorporated herein by reference in its entirety).

Simultaneous deprotection of pinane ester and salicylic acid protectivegroups of compounds of formula VI can be achieved by heating with diluteHCl, affording the desired compounds of structure Ib. Thistransformation may also be achieved by treatment with BCl₃ or BBr₃(WO09064414), which is incorporated herein by reference in its entirety.Alternatively, the deprotection may be attained via transesterificationwith isobutyl boronic acid in presence of dilute acid (WO09064413, whichis incorporated herein by reference in its entirety) or via other knownmethods (J. Org. Chem. (2010), 75, 468-471, which is incorporated hereinby reference in its entirety).

Salicylic acid derivatives of formula A′ where Y′ is a leaving groupundergo coupling reaction with Reformatsky reagent of acetate in Negishiconditions to give intermediates of formula VII where X′ is OR′″(Tetrahedron, 2014, 1508-1515, J. Org. Chem., 2013, 78, 8250-8266, whichis incorporated herein by reference in its entirety) (Scheme 2). Suchintermediates may be alkylated with halomethylene boronate derivative(VIIA) to give compounds of formula VIII in high stereoselectivity (J.Am. Chem. Soc., 2011, 133, 11936-11939, which is incorporated herein byreference in its entirety). Intermediates of formula VII undergomethylenation to give derivatives of IX (J. Org. Chem., 1986, 51,2981-2988, which is incorporated herein by reference in its entirety).Intermediates of formula IX undergo asymmetric boronation in knownconditions to give compounds of formula VIII (J. Am. Chem. Soc., 2010,132, 10630-10633, which is incorporated herein by reference in itsentirety). Such asymmetric boronation may also feasible where X′ is—NR¹R². Intermediates of formula VIII can be further transformed tocompound of formula Ib under the conditions described in scheme 1.

In an alternative sequence, compounds of formula Ib can be made viaboracarboxylation followed by asymmetric hydrogenation of acetyleneintermediate X as shown in scheme 3. Aryl or heteroaryl derivativesformula A′ can undergo Pd mediated coupling reaction to give acetylenesubstituted compound with TMS-acetylene. Boracarboxylation of alkyneswith a diborane compound and carbon dioxide in presence of anN-heterocyclic carbene copper (I) complex as a catalyst givesα,β-unsaturated β-boralactone derivatives regio- and stereoselectivelyvia a borylcupration/carboxylation (J. Am. Chem. Soc. 2012, 134,14314-14317, which is incorporated herein by reference in its entirety).Such resulting derivatives can be transformed to esters of carboxylateand boronate to give intermediates of formula XI. Asymmetrichydrogenation of intermediates of formula XI (Chem. Rev. 2003, 103,3029-3070, which is incorporated herein by reference in its entirety)may be utilized to give enatiomerically pure compounds of XII. Suchcompounds may be further transformed to compounds of formula Ib via VIby derivatization and hydrolysis as described above in scheme 1.

Compounds of formula Ib where Y¹═CH, Y²═—NHC(O)— may be prepared fromcarboxylic acid of formula XII (R′″═OH) as shown in scheme 4. Suchcompounds may be converted to amides via Curtius rearrangement (Chem.Rev. 1988, 88, 297-368; Org. Lett., 2005, 4107-4110, which isincorporated herein by reference in its entirety) followed bydeprotection, amide formation to give compounds of formula XIV.Compounds of formula XIII may also be transformed to compounds offormula Ib where Y² is —NHC(O)—O— by hydrolysis.

Intermediates of formula XVII to attain compounds of formula Ib may beprepared as shown in scheme 5. Such intermediates of formula XVII can besynthesized from XIV where X′ is a triflate or bromo or iodo group byutilizing Reformatsky reagent of bromomethylene acetate ester (J. Org.Chem., 2013, 78, 8250-8266; Chem Lett., 1993, 845-848, which isincorporated herein by reference in its entirety). Compounds where X′ issubstituted with bromo or iodo groups can be attained from appropriatelyprotected commercial 2,5-hydroxy-benzoic acid derivatives (J. Med.Chem., 2003, 46, 3437-3440, which is incorporated herein by reference inits entirety). Intermediates of XIV can also be prepared viacarboxylation of derivatives of formula XV where Z′ is a fluoro or OR′or SR′ by earlier described methods (WO12106995, which is incorporatedherein by reference in its entirety).

In another exemplary synthetic scheme 6, the compound of formula XX canbe prepared from a salicylic acid derivative of formula XVIII. Thecompounds of formula XVIII upon diallylation under basic conditionsfollowed by thermal Claisen rearrangement (Org. React. 1975, 22, 1-252,which is incorporated herein by reference in its entirety) and esterhydrolysis give compounds of formula XIX. Such compounds upon protectionand oxidation followed by esterification result in phenylacetic acidcompounds of formula XX. Compounds of formula XX can be furthertransformed as shown above in scheme 2. The compound of formula XVIIIcan also undergo the steps listed above in Scheme 5 to form anortho-carboxylate-substituted compound of formula XIX.

Synthesis of Prodrugs

Compounds of formula Ib where the R is a prodrug moiety may besynthesized by a variety of known methods of different carboxylic acidprodrugs (Prodrugs: Challenges and Rewards, V. J. Stella, et al., ed.,Springer, New York, 2007, which is incorporated herein by reference inits entirety). These prodrugs include but are not limited to substitutedor non-substituted alkyl esters, (acyloxy)alkyl (Synthesis 2012, 44,207, which is incorporated herein by reference in its entirety),[(alkoxycarbonyl)oxy]methyl esters (WO10097675, which is incorporatedherein by reference in its entirety), or (oxodioxolyl)methyl esters (J.Med. Chem. 1996, 39, 323-338, which is incorporated herein by referencein its entirety). Such prodrugs can be made from compounds of formula Ibwhere R═H by treatment with acid or in neutral conditions (e.g.,carbodiimide coupling) in the presence of alcohols (ROH) or via basepromoted esterification with RX where X is a leaving group in thepresence of an appropriate base.

One exemplary but non-limiting general synthetic scheme for preparingprodrugs is shown in Scheme 7 below. The boronic acid of Formula Ibwhere R is hydrogen can react with a chloro/bromo-substituted prodrugmoiety to form a prodrug of Formula Ib where R is a prodrug moiety.Examples of the prodrug moiety R can be —C₁₋₉alkyl,—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, and

Alternatively, boronate esters of formula XXI or correspondingtetrafluoroborates (Chem. Rev. 2008, 108, 288-325, which is incorporatedherein by reference in its entirety) may be also utilized forintroduction of prodrugs and convert them to final prodrugs (Scheme 8).Such carboxylic acids (XXI) can be made from compounds of formula VI byselective deprotection of OR′. The prodrug group may also be introducedearlier in the sequence in compounds of formula V where R′ is R. Suchsequence where prodrug is introduced in earlier intermediates is onlyfeasible when the ester is stable under the final deprotectionconditions to remove the phenol protective group and boronate estergroup.

Compounds of Formula IIIC may be prepared as shown in scheme 9.Compounds of formula IIIc where m is 0 and Y⁷ is —CH₂— may besynthesized via intermediate A′ by coupling of vinyl boronate in Heckreaction conditions (J. Med. Chem., 2015, 58, 147-169, which isincorporated herein by reference in its entirety) or by coupling of anacetylene derivative of protected boronate via Sonagashira conditions(Tet., 2011, 67, 4306-4312, which is incorporated herein by reference inits entirety). The protection of such boronate substitutedvinyl/acetylene intermediates can be selected from pinacol or pinanediolor dimethylaminonaphthalene (Org. Lett., 2008, 10, 377-380, which isincorporated herein by reference in its entirety) or MIDA (J. Am. Chem.Soc., 2009, 131, 6961-6963, which is incorporated herein by reference inits entirety) groups. The resulting coupling products can behydrogenated under catalytic conditions to give intermediate XXIII whichcan be further transformed to compounds of formula IIIc as describedearlier in scheme 1 or by other methods known in the art. Alternatively,aryl intermediates of formula A′ of desired substitution can beconverted to vinyl substituted intermediates such as XXII which readilyundergo Ir (Tetrahedron, 2004, 60, 10695-10700, which is incorporatedherein by reference in its entirety) or Cu (Tetrahedron Lett., 2015, 56,2297-2302, which is incorporated herein by reference in its entirety)mediated borylation to form intermediates of formula XXIII. Compounds offormula XXIII can also be made from acetylene substituted compounds offormula X via borylation of corresponding lithiated acetylide (Angew.Chem., Int. Ed., 2012, 51, 2947-2950, which is incorporated herein byreference in its entirety) or in a Pd catalyzed reaction (Org. Lett.,2016, 18, 432-435, which is incorporated herein by reference in itsentirety) followed by hydrogenation of resulting products. Arylintermediates of formula A′ where Y′═H can be utilized via Claisenrearrangement (Chem. Rev., 2004, 104, 2939-3002, which is incorporatedherein by reference in its entirety). Allyl ethers of A′ intermediatewhere R″ is allyl undergo Claisen rearrangement. Such rearrangementproducts can be converted to haloethylene substitution via ozonolysis orperiodate reaction of terminal olefin to aldehydes followed by reductionand conversion of resulting alcohols to halides. These primary orsecondary halides can be transformed to boronate esters of formula XXIIIunder a variety of conditions including via reactions catalyzed by Cu(Angew. Chem. Int. Ed., 2012, 51, 528-532; and Org. Lett., 2012, 14,890-893, which are incorporated herein by reference in theirentireties), Pd (J. Org. Chem., 2012, 77, 6629-6633, which isincorporated herein by reference in its entirety), Fe (J. Am. Chem.Soc., 2014, 136, 9521-9523, which is incorporated herein by reference inits entirety) Zn (Angew. Chem. Int. Ed. 2014, 53, 1799-1803), Ni (J. Am.Chem. Soc., 2012, 134, 10693-10697, which is incorporated herein byreference in its entirety). Compounds of formula IIIC where m=1 and Y isO, S or NR′ can be synthesized through intermediate XXIV where Y′ is—OH, —SH or —NHR, by alkylation of bromo/iodomethylene boronate ester ofpinacol or pinanediol (WO 09046098, which is incorporated herein byreference in its entirety) (Scheme 9).

A non-limiting example for makng compounds of formula IIIc is shown inScheme 10. Compounds of formula IIIc-1 where M is R⁵ is—(CH₂)_(p)—Y³—(CH₂)_(q)M can be made from intermediates of formula XXVI.Such compounds of XXVI can be made from XXV where R⁵ is alreadyintroduced. Alternatively, R⁵ can also be substituted at XXVI stage bydeprotection of —OR′ or SR′ or CR¹R²OR¹, CR¹R²SR¹, CR¹R²NHR′ andreaction with appropriate protected building blocks of R⁵ (scheme 10).Compounds of formula IIIc wherein J and/or L is R⁵ is—(CH₂)_(p)—Y³—(CH₂)_(q)M can also be made from the appropriateintermediates XXV and XXVI using this scheme.

Administration and Pharmaceutical Compositions

The compounds are administered at a therapeutically effective dosage.While human dosage levels have yet to be optimized for the compoundsdescribed herein, generally, a daily dose may be from about 0.25 mg/kgto about 120 mg/kg or more of body weight, from about 0.5 mg/kg or lessto about 70 mg/kg, from about 1.0 mg/kg to about 50 mg/kg of bodyweight, or from about 1.5 mg/kg to about 10 mg/kg of body weight. Thus,for administration to a 70 kg person, the dosage range would be fromabout 17 mg per day to about 8000 mg per day, from about 35 mg per dayor less to about 7000 mg per day or more, from about 70 mg per day toabout 6000 mg per day, from about 100 mg per day to about 5000 mg perday, or from about 200 mg to about 3000 mg per day. The amount of activecompound administered will, of course, be dependent on the subject anddisease state being treated, the severity of the affliction, the mannerand schedule of administration and the judgment of the prescribingphysician.

Administration of the compounds disclosed herein or the pharmaceuticallyacceptable salts thereof can be via any of the accepted modes ofadministration for agents that serve similar utilities including, butnot limited to, orally, subcutaneously, intravenously, intranasally,topically, transdermally, intraperitoneally, intramuscularly,intrapulmonarilly, vaginally, rectally, or intraocularly. Oral andparenteral administrations are customary in treating the indicationsthat are the subject of the preferred embodiments.

The compounds useful as described above can be formulated intopharmaceutical compositions for use in treatment of these conditions.Standard pharmaceutical formulation techniques are used, such as thosedisclosed in Remington's The Science and Practice of Pharmacy, 21st Ed.,Lippincott Williams & Wilkins (2005), incorporated by reference in itsentirety. Accordingly, some embodiments include pharmaceuticalcompositions comprising: (a) a safe and therapeutically effective amountof a compound described herein (including enantiomers, diastereoisomers,tautomers, polymorphs, and solvates thereof), or pharmaceuticallyacceptable salts thereof; and (b) a pharmaceutically acceptable carrier,diluent, excipient or combination thereof.

In addition to the selected compound useful as described above, comeembodiments include compositions containing apharmaceutically-acceptable carrier. The term “pharmaceuticallyacceptable carrier” or “pharmaceutically acceptable excipient” includesany and all solvents, dispersion media, coatings, antibacterial andantifungal agents, isotonic and absorption delaying agents and the like.The use of such media and agents for pharmaceutically active substancesis well known in the art. Except insofar as any conventional media oragent is incompatible with the active ingredient, its use in thetherapeutic compositions is contemplated. In addition, various adjuvantssuch as are commonly used in the art may be included. Considerations forthe inclusion of various components in pharmaceutical compositions aredescribed, e.g., in Gilman et al. (Eds.) (1990); Goodman and Gilman's:The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press,which is incorporated herein by reference in its entirety.

Some examples of substances, which can serve aspharmaceutically-acceptable carriers or components thereof, are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents;flavoring agents; tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

The compositions described herein are preferably provided in unit dosageform. As used herein, a “unit dosage form” is a composition containingan amount of a compound that is suitable for administration to ananimal, preferably mammal subject, in a single dose, according to goodmedical practice. The preparation of a single or unit dosage formhowever, does not imply that the dosage form is administered once perday or once per course of therapy. Such dosage forms are contemplated tobe administered once, twice, thrice or more per day and may beadministered as infusion over a period of time (e.g., from about 30minutes to about 2-6 hours), or administered as a continuous infusion,and may be given more than once during a course of therapy, though asingle administration is not specifically excluded. The skilled artisanwill recognize that the formulation does not specifically contemplatethe entire course of therapy and such decisions are left for thoseskilled in the art of treatment rather than formulation.

The compositions useful as described above may be in any of a variety ofsuitable forms for a variety of routes for administration, for example,for oral, nasal, rectal, topical (including transdermal), ocular,intracerebral, intracranial, intrathecal, intra-arterial, intravenous,intramuscular, or other parental routes of administration. The skilledartisan will appreciate that oral and nasal compositions comprisecompositions that are administered by inhalation, and made usingavailable methodologies. Depending upon the particular route ofadministration desired, a variety of pharmaceutically-acceptablecarriers well-known in the art may be used. Pharmaceutically-acceptablecarriers include, for example, solid or liquid fillers, diluents,hydrotropies, surface-active agents, and encapsulating substances.Optional pharmaceutically-active materials may be included, which do notsubstantially interfere with the inhibitory activity of the compound.The amount of carrier employed in conjunction with the compound issufficient to provide a practical quantity of material foradministration per unit dose of the compound. Techniques andcompositions for making dosage forms useful in the methods describedherein are described in the following references, all incorporated byreference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10(Banker & Rhodes, editors, 2002); Lieberman et al., PharmaceuticalDosage Forms: Tablets (1989); and Ansel, Introduction to PharmaceuticalDosage Forms 8th Edition (2004).

Various oral dosage forms can be used, including such solid forms astablets, capsules, granules and bulk powders. Tablets can be compressed,tablet triturates, enteric-coated, sugar-coated, film-coated, ormultiple-compressed, containing suitable binders, lubricants, diluents,disintegrating agents, coloring agents, flavoring agents, flow-inducingagents, and melting agents. Liquid oral dosage forms include aqueoussolutions, emulsions, suspensions, solutions and/or suspensionsreconstituted from non-effervescent granules, and effervescentpreparations reconstituted from effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, melting agents, coloring agents and flavoringagents.

The pharmaceutically-acceptable carrier suitable for the preparation ofunit dosage forms for peroral administration is well-known in the art.Tablets typically comprise conventional pharmaceutically-compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules typically comprise oneor more solid diluents disclosed above. The selection of carriercomponents depends on secondary considerations like taste, cost, andshelf stability, which are not critical, and can be readily made by aperson skilled in the art.

Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; typicalwetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the subject compound isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragitcoatings, waxes and shellac.

Compositions described herein may optionally include other drug actives.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol; and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose and hydroxypropylmethyl cellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

A liquid composition, which is formulated for topical ophthalmic use, isformulated such that it can be administered topically to the eye. Thecomfort should be maximized as much as possible, although sometimesformulation considerations (e.g. drug stability) may necessitate lessthan optimal comfort. In the case that comfort cannot be maximized, theliquid should be formulated such that the liquid is tolerable to thepatient for topical ophthalmic use. Additionally, an ophthalmicallyacceptable liquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositionsdisclosed herein include, but are not limited to, benzalkonium chloride,PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations disclosed herein. These vehicles include, but are notlimited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose,poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purifiedwater.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. For manycompositions, the pH will be between 4 and 9. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant includes,but is not limited to, sodium metabisulfite, sodium thiosulfate,acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

Other excipient components, which may be included in the ophthalmicpreparations, are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,co-solvent, emulsifier, penetration enhancer, preservative system, andemollient.

For intravenous administration, the compounds and compositions describedherein may be dissolved or dispersed in a pharmaceutically acceptablediluent, such as a saline or dextrose solution. Suitable excipients maybe included to achieve the desired pH, including but not limited toNaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In variousembodiments, the pH of the final composition ranges from 2 to 8, orpreferably from 4 to 7. Antioxidant excipients may include sodiumbisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate,thiourea, and EDTA. Other non-limiting examples of suitable excipientsfound in the final intravenous composition may include sodium orpotassium phosphates, citric acid, tartaric acid, gelatin, andcarbohydrates such as dextrose, mannitol, and dextran. Furtheracceptable excipients are described in Powell, et al., Compendium ofExcipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998,52 238-311 and Nema et al., Excipients and Their Role in ApprovedInjectable Products: Current Usage and Future Directions, PDA J PharmSci and Tech 2011, 65 287-332, both of which are incorporated herein byreference in their entirety. Antimicrobial agents may also be includedto achieve a bacteriostatic or fungistatic solution, including but notlimited to phenylmercuric nitrate, thimerosal, benzethonium chloride,benzalkonium chloride, phenol, cresol, and chlorobutanol.

The compositions for intravenous administration may be provided tocaregivers in the form of one more solids that are reconstituted with asuitable diluent such as sterile water, saline or dextrose in watershortly prior to administration. In other embodiments, the compositionsare provided in solution ready to administer parenterally. In stillother embodiments, the compositions are provided in a solution that isfurther diluted prior to administration. In embodiments that includeadministering a combination of a compound described herein and anotheragent, the combination may be provided to caregivers as a mixture, orthe caregivers may mix the two agents prior to administration, or thetwo agents may be administered separately.

The actual dose of the active compounds described herein depends on thespecific compound, and on the condition to be treated; the selection ofthe appropriate dose is well within the knowledge of the skilledartisan.

Methods of Treatment

Some embodiments of the present invention include methods of treatingbacterial infections with the compounds and compositions comprising thecompounds described herein. Some methods include administering acompound, composition, pharmaceutical composition described herein to asubject in need thereof. In some embodiments, a subject can be ananimal, e.g., a mammal (including a human). In some embodiments, thebacterial infection comprises a bacteria described herein. As will beappreciated from the foregoing, methods of treating a bacterialinfection include methods for preventing bacterial infection in asubject at risk thereof.

In some embodiments, the subject is a human.

Further embodiments include administering a combination of compounds toa subject in need thereof. A combination can include a compound,composition, pharmaceutical composition described herein with anadditional medicament.

Some embodiments include co-administering a compound, composition,and/or pharmaceutical composition described herein, with an additionalmedicament. By “co-administration,” it is meant that the two or moreagents may be found in the patient's bloodstream at the same time,regardless of when or how they are actually administered. In oneembodiment, the agents are administered simultaneously. In one suchembodiment, administration in combination is accomplished by combiningthe agents in a single dosage form. In another embodiment, the agentsare administered sequentially. In one embodiment the agents areadministered through the same route, such as orally. In anotherembodiment, the agents are administered through different routes, suchas one being administered orally and another being administered i.v.

Examples of additional medicaments include an antibacterial agent,antifungal agent, an antiviral agent, an anti-inflammatory agent and ananti-allergic agent.

Preferred embodiments include combinations of a compound, composition orpharmaceutical composition described herein with an antibacterial agentsuch as a β-lactam. Examples of such β-lactams include Amoxicillin,Ampicillin (e.g., Pivampicillin, Hetacillin, Bacampicillin,Metampicillin, Talampicillin), Epicillin, Carbenicillin (Carindacillin),Ticarcillin, Temocillin, Azlocillin, Piperacillin, Mezlocillin,Mecillinam (Pivmecillinam), Sulbenicillin, Benzylpenicillin (G),Clometocillin, Benzathine benzylpenicillin, Procaine benzylpenicillin,Azidocillin, Penamecillin, Phenoxymethylpenicillin (V), Propicillin,Benzathine phenoxymethylpenicillin, Pheneticillin, Cloxacillin (e.g.,Dicloxacillin, Flucloxacillin), Oxacillin, Methicillin, Nafcillin,Faropenem, Biapenem, Doripenem, Ertapenem, Imipenem, Meropenem,Panipenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin,Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone,Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole,Cefminox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone,Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef,Cefixime, Ceftazidime, Ceftriaxone, Cefeapene, Cefdaloxime, Cefdinir,Cefditoren, Cefetamet, Cefmenoxime, Cefodizime, Cefoperazone,Cefotaxime, Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram,Ceftibuten, Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime,Cefozopran, Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, Ceftiofur,Cefquinome, Cefovecin, Aztreonam, Tigemonam and Carumonam.

Preferred embodiments include β-lactams such as Ceftazidime, Biapenem,Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Tebipenem pivoxil,Apapenem, and Panipenem.

Additional preferred embodiments include β-lactams such as Aztreonam,Tigemonam, and Carumonam.

Some embodiments include a combination of the compounds, compositionsand/or pharmaceutical compositions described herein with an additionalagent, wherein the additional agent comprises a monobactam. Examples ofmonobactams include aztreonam, tigemonam, nocardicin A, carumonam, andtabtoxin. In some such embodiments, the compound, composition and/orpharmaceutical composition comprises a class A, C, or D beta-lactamaseinhibitor. Some embodiments include co-administering the compound,composition or pharmaceutical composition described herein with one ormore additional agents.

Some embodiments include a combination of the compounds, compositionsand/or pharmaceutical compositions described herein with an additionalagent, wherein the additional agent comprises a class B beta lactamaseinhibitor. An example of a class B beta lactamase inhibitor includesME1071 (Yoshikazu Ishii et al, “In Vitro Potentiation of Carbapenemswith ME1071, a Novel Metallo-β-Lactamase Inhibitor, againstMetallo-β-lactamase Producing Pseudomonas aeruginosa Clinical Isolates.”Antimicrob. Agents Chemother. doi:10.1128/AAC.01397-09 (July 2010)).Some embodiments include co-administering the compound, composition orpharmaceutical composition described herein with one or more additionalagents.

Some embodiments include a combination of the compounds, compositionsand/or pharmaceutical compositions described herein with an additionalagent, wherein the additional agent comprises one or more agents thatinclude a class A, B, C, or D beta lactamase inhibitor. Some embodimentsinclude co-administering the compound, composition or pharmaceuticalcomposition described herein with the one or more additional agents.

Indications

The compounds and compositions comprising the compounds described hereincan be used to treat bacterial infections. Bacterial infections that canbe treated with the compounds, compositions and methods described hereincan comprise a wide spectrum of bacteria. Example organisms includegram-positive bacteria, gram-negative bacteria, aerobic and anaerobicbacteria, such as Staphylococcus, Lactobacillus, Streptococcus, Sarcina,Escherichia, Enterobacter, Klebsiella, Pseudomonas, Acinetobacter,Mycobacterium, Proteus, Campylobacter, Citrobacter, Nisseria, Baccillus,Bacteroides, Peptococcus, Clostridium, Salmonella, Shigella, Serratia,Haemophilus, Brucella and other organisms.

More examples of bacterial infections include Pseudomonas aeruginosa,Pseudomonas fluorescens, Pseudomonas acidovorans, Pseudomonasalcaligenes, Pseudomonas putida, Stenotrophomonas maltophilia,Burkholderia cepacia, Aeromonas hydrophilia, Escherichia coli,Citrobacter freundii, Salmonella typhimurium, Salmonella typhi,Salmonella paratyphi, Salmonella enteritidis, Shigella dysenteriae,Shigella flexneri, Shigella sonnei, Enterobacter cloacae, Enterobacteraerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratiamarcescens, Francisella tularensis, Morganella morganii, Proteusmirabilis, Proteus vulgaris, Providencia alcalifaciens, Providenciarettgeri, Providencia stuartii, Acinetobacter baumannii, Acinetobactercalcoaceticus, Acinetobacter haemolyticus, Yersinia enterocolitica,Yersinia pestis, Yersinia pseudotuberculosis, Yersinia intermedia,Bordetella pertussis, Bordetella parapertussis, Bordetellabronchiseptica, Haemophilus influenzae, Haemophilus parainfluenzae,Haemophilus haemolyticus, Haemophilus parahaemolyticus, Haemophilusducreyi, Pasteurella multocida, Pasteurella haemolytica, Branhamellacatarrhalis, Helicobacter pylori, Campylobacter fetus, Campylobacterjejuni, Campylobacter coli, Borrelia burgdorferi, Vibrio cholerae,Vibrio parahaemolyticus, Legionella pneumophila, Listeria monocytogenes,Neisseria gonorrhoeae, Neisseria meningitidis, Kingella, Moraxella,Gardnerella vaginalis, Bacteroides fragilis, Bacteroides distasonis,Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroidesovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroideseggerthii, Bacteroides splanchnicus, Clostridium difficile,Mycobacterium tuberculosis, Mycobacterium avium, Mycobacteriumintracellulare, Mycobacterium leprae, Corynebacterium diphtheriae,Corynebacterium ulcerans, Streptococcus pneumoniae, Streptococcusagalactiae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcusfaecium, Staphylococcus aureus, Staphylococcus epidermidis,Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcushyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcushominis, or Staphylococcus saccharolyticus.

To further illustrate this invention, the following examples areincluded. The examples should not, of course, be construed asspecifically limiting the invention. Variations of these examples withinthe scope of the claims are within the purview of one skilled in the artand are considered to fall within the scope of the invention asdescribed, and claimed herein. The reader will recognize that theskilled artisan, armed with the present disclosure, and skill in the artis able to prepare and use the invention without exhaustive examples.The following examples will further describe the present invention, andare used for the purposes of illustration only, and should not beconsidered as limiting.

EXAMPLES General Procedures

Materials used in preparing the cyclic boronic acid ester derivativesdescribed herein may be made by known methods or are commerciallyavailable. It will be apparent to the skilled artisan that methods forpreparing precursors and functionality related to the compounds claimedherein are generally described in the literature including, for example,procedures described in U.S. Pat. No. 7,271,186 and WO2009064414, eachof which is incorporated by reference in its entirety. In thesereactions, it is also possible to make use of variants which arethemselves known to those of ordinary skill in this art, but are notmentioned in greater detail. The skilled artisan given the literatureand this disclosure is well equipped to prepare any of the compounds.

It is recognized that the skilled artisan in the art of organicchemistry can readily carry out manipulations without further direction,that is, it is well within the scope and practice of the skilled artisanto carry out these manipulations. These include reduction of carbonylcompounds to their corresponding alcohols, oxidations, acylations,aromatic substitutions, both electrophilic and nucleophilic,etherifications, esterification and saponification and the like. Thesemanipulations are discussed in standard texts such as March AdvancedOrganic Chemistry (Wiley), Carey and Sundberg, Advanced OrganicChemistry (incorporated herein by reference in their entirety) and thelike.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other functionality is masked or protected in themolecule, thus avoiding any undesirable side reactions and/or increasingthe yield of the reaction. Often the skilled artisan utilizes protectinggroups to accomplish such increased yields or to avoid the undesiredreactions. These reactions are found in the literature and are also wellwithin the scope of the skilled artisan. Examples of many of thesemanipulations can be found for example in T. Greene and P. WutsProtecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons(2007), incorporated herein by reference in its entirety.

The following example schemes are provided for the guidance of thereader, and represent preferred methods for making the compoundsexemplified herein. These methods are not limiting, and it will beapparent that other routes may be employed to prepare these compounds.Such methods specifically include solid phase based chemistries,including combinatorial chemistry. The skilled artisan is thoroughlyequipped to prepare these compounds by those methods given theliterature and this disclosure. The compound numberings used in thesynthetic schemes depicted below are meant for those specific schemesonly, and should not be construed as or confused with same numberings inother sections of the application.

Trademarks used herein are examples only and reflect illustrativematerials used at the time of the invention. The skilled artisan willrecognize that variations in lot, manufacturing processes, and the like,are expected. Hence the examples, and the trademarks used in them arenon-limiting, and they are not intended to be limiting, but are merelyan illustration of how a skilled artisan may choose to perform one ormore of the embodiments of the invention.

The following abbreviations have the indicated meanings:

-   -   DCM=dichloromethane    -   DMF=N,N-dimethylformamide    -   ESBL=extended-spectrum β-lactamase    -   EtOAc=ethyl acetate    -   HATU=2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium        hexafluorophosphate    -   MeCN=acetonitrile    -   NMR=nuclear magnetic resonance    -   TBDMSCl=tert-butyldimethylsilyl chloride    -   TBS=tert-butyldimethylsilyl    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   TLC=thin layer chromatography

The following example schemes are provided for the guidance of thereader, and collectively represent an example method for making thecompounds provided herein. Furthermore, other methods for preparingcompounds described herein will be readily apparent to the person ofordinary skill in the art in light of the following reaction schemes andexamples. Unless otherwise indicated, all variables are as definedabove.

Example 12-HYDROXY-4-(2-(THIOPHEN-2-YL)ACETAMIDO)-3,4-DIHYDRO-2H-BENZO[E][1,2]OXABORININE-8-CARBOXYLICACID (1)

Step 1: Synthesis of Compound 1B

To the solution of compound 1A (200 g, 1.314 mol) in THF (500 mL) wasadded Boc₂O (1146 g, 5.26 mol), DMAP (48 g, 0.394 mol) and ^(t)BuOH (1L). The resulting solution was stirred at 60° C. for 6 hours before itwas concentrated in vacuo. The residue was purified by flash columnchromatography (ethyl acetate/hexanes, v/v, 1/200˜1/100) to give thetitle compound 1B (192.8 g, 47.6% yield) as colorless oil.

¹H-NMR: (400 MHz, CDCl₃) δ 7.73 (d, 1H), 7.35 (d, 1H), 7.15 (t, 1H),2.25 (s, 3H), 1.60 (s, 9H), 1.58 (s, 9H).

Step 2: Synthesis of Compound 1C

To the solution of compound 1B (192.8 g, 625 mmol) and NBS (122.4 g, 688mmol) in CCl₄ (1 L) was added BPO (15.1 g, 62.5 mmol). The resultingmixture was refluxed at 80° C. for 15 hours. The solid was filtered offand the filtrate was concentrated in vacuo. The residue wasrecrystallized with hexanes to afford the title compound 1C (141 g,58.2% yield) as white solid.

¹H-NMR: (400 MHz, CDCl₃) δ 7.87 (d, 1H), 7.55 (d, 1H), 7.26 (t, 1H),4.49 (s, 2H), 1.59 (s, 9H), 1.55 (s, 9H).

Step 3: Synthesis of Compound 1D

To the suspension of CuI (480 mg, 2.51 mmol) in THF (100 mL) was addedvinylmagnesium bromide (12.6 mL, 1.0M in THF, 12.6 mmol) dropwise at−50° C. in 5 minutes. After 10 minutes, a solution of compound 1C (3.24g, 8.37 mmol) in THF (20 mL) was added via syringe in 3 minutes. Theresulting reaction mixture was slowly warmed up to room temperature in 3hours and stirred overnight. The dark reaction mixture was quenched withsaturated NH₄Cl and extracted with EtOAc twice. After drying overNa₂SO₄, the organic solution was concentrated and chromatographed (ethylacetate/hexanes, v/v, 1/20˜1/8) to obtain the title compound 1D (1.81 g,65% yield) as slightly yellow oil.

¹H-NMR: (300 MHz, CDCl₃) δ 7.78 (dd, 1H), 7.38 (dd, 1H), 7.20 (t, 1H),5.80-5.96 (m, 1H), 5.08 (d, 1H), 5.03 (s, 1H), 3.39 (d, 2H), 1.59 (s,9H), 1.56 (s, 9H).

Step 4: Synthesis of Compound 1E

To a solution of 1D (2.0 g, 6.0 mmol) in CH₂Cl₂ (35 mL) and MeOH (5 mL)at −78° C. was bubbled with O₃ until light blue color appeared in theflask. Then Me₂S (2.64 mL, 36 mmol) was added, and the solution wasslowly warmed up to room temperature where it was stirred for 16 h. Thereaction solution was concentrated in vacuo to dryness and used directlyfor next step.

Step 5: Synthesis of Compound 1F

To a solution of crude 1E (about 6.0 mmol) in THF (80 mL), t-BuOH (35mL) and water (35 mL) at 0° C. was added 2-methyl-2-butene (6.4 mL, 60mmol), followed by NaClO₂ (3.26 g, ˜80% purity, 36 mmol). After 30 minat 0° C., then reaction was quenched with NaHSO₃ (5 g). The solution wasadjusted to pH=2 with 1N HCl, and extracted with EtOAc twice. Thecombined organic layers were washed with brine and dried over Na₂SO₄.After concentration, 1.2 g crude 1F was obtained as light yellow oil,which was used directly for next step.

¹H-NMR: (300 MHz, CDCl₃) δ 7.83 (dd, 1H), 7.43 (dd, 1H), 7.22 (t, 1H),3.66 (s, 2H), 1.57 (s, 9H), 1.53 (s, 9H).

Step 6: Synthesis of Compound 1G

To a solution of crude 1F (about 3.4 mmol) in MeCN (9 mL) was added BnBr(0.81 mL, 6.8 mmol), followed by Et₃N (0.71 mL, 5.1 mmol). The resultingsolution was stirred at room temperature for 6 hours. The reactionmixture was diluted with EtOAc and washed with water and brine. Theaqueous layers were extracted with EtOAc. The combined organic layerswere dried over Na₂SO₄. After concentration, the residue was purified bycolumn chromatography (ethyl acetate/hexanes, v/v, 1/10˜1/3) to obtainthe title compound 1G (0.82 g) as slightly yellow oil.

¹H-NMR: (300 MHz, CDCl₃) δ 7.82 (d, 1H), 7.43 (d, 1H), 7.25-7.36 (m,5H), 7.21 (t, 1H), 5.12 (s, 2H), 3.70 (s, 2H), 1.56 (s, 9H), 1.52 (s,9H).

Step 7: Synthesis of Compound 1H

To the solution of 1G (5.9 g, 13.3 mmol) in THF (50 mL) was added LDA(freshly made from diisopropylamine (2.43 g, 17.3 mmol) and n-BuLi (6.65mL, 2.5 M in hexanes, 16.6 mmol) in 30 mL THF, pre-cooled to −78° C.) at−78° C. via cannula. After 5 minutes, bromomethylboronic acid pinacolester (4.1 g, 18.6 mmol) was added via syringe. After 30 minutes at −78°C., ZnCl₂ (30 mL, 1M in Et₂O, 30 mmol) was added slowly in 5 minutes.The resulting solution was slowly warmed up to room temperature for 3hours before it was quenched with saturated NH₄Cl. The reaction mixturewas extracted with EtOAc twice and dried over Na₂SO₄. Afterconcentration, the residue was purified by column chromatography (ethylacetate/hexanes, v/v, 1/10˜1/5) to obtain the title compound 1H (4.7 g)as slightly yellow oil.

¹H-NMR: (300 MHz, CDCl₃) δ 7.80 (d, 1H), 7.42 (d, 1H), 7.20-7.36 (m,5H), 7.20 (t, 1H), 4.92-5.19 (dd, 2H), 4.22 (dd, 1H), 1.58 (s, 9H), 1.55(s, 9H), 1.24 (d, 2H), 1.15 (d, 12H).

Step 8: Synthesis of Compound 11

Compound 1H (4.7 g, 8.1 mmol) and (+)-pinanediol (1.65 g, 9.7 mmol) werestirred in THF (50 mL) at room temperature for 24 hours. The reactionmixture was concentrated and purified by column chromatography (ethylacetate/hexanes, v/v, 1/10˜1/5) to obtain the title compound 11 (2.8 g)as slightly yellow oil.

¹H-NMR: (300 MHz, CDCl₃) δ 7.80 (d, 1H), 7.42 (d, 1H), 7.18-7.36 (m,5H), 7.18 (t, 1H), 4.92-5.21 (m, 2H), 4.24 (m, 1H), 4.18 (m, 1H),2.17-2.32 (m, 1H), 2.00-2.16 (m, 1H), 1.92-2.00 (m, 1H), 1.65-1.86 (m,2H), 1.60 (s, 9H), 1.51 (s, 9H), 1.22-1.31 (m, 5H), 1.12-1.16 (m, 3H),0.77-0.84 (m, 3H).

Step 9: Synthesis of Compound 1J

Compound 11 (2.8 g, 4.4 mmol) and Pd/C (400 mg, 10%) were stirred inEtOAc (50 mL) at room temperature under hydrogen (1 atm) for 18 hours.The reaction mixture was filtered through Celite and washed with EtOAc.After concentration, the mixture was purified by column chromatography(ethyl acetate/hexanes, v/v, 1/2˜1/1) to obtain the title compound 1J(1.48 g) as white solid.

MS calcd for (C₂₉H₄₁BO₉): 544MS (ESI, negative) found: (M−1): 543

Step 10: Synthesis of Compound 1K

Compound 1J (1.26 g, 2.3 mmol), DPPA (0.65 mL, 3.0 mmol) and Et₃N (0.48mL, 3.5 mmol) were dissolved in dry toluene (12 mL) at room temperaturein nitrogen atmosphere. After 30 minutes, BnOH (2.4 mL, 23 mmol) wasadded and the reaction mixture was heated to 80° C. and stirred at thistemperature for 16 hours. After cooling down, the solution wasconcentrated and purified by column chromatography (ethylacetate/hexanes, v/v, 1/4˜1/3) to obtain the title compound 1K (0.88 g)as colorless oil.

MS calcd for (C₃₆H₄₈BNO₉): 649MS (ESI, positive) found: (M+1): 650MS (ESI, negative) found: (M−1): 648

Step 11: Synthesis of Compound 1L

To the solution of 1K (170 mg, 0.26 mmol) in 10 mL dioxane was addedPd/C (80 mg, 10%) and HCl solution (0.13 mL, 4 N in dioxane, 0.53 mmol).The resulting mixture was stirred at room temperature under hydrogen (1atm) atmosphere for 2 hours. The reaction mixture was filtered throughCelite and washed with dioxane. The filtrate was directly used for nextstep.

MS calcd for (C₂₈H₄₂BNO₇): 515MS (ESI, positive) found: (M+1): 516

Step 12: Synthesis of Compound 1M

To the solution of 2-thiopheneacetic acid (75 mg, 0.53 mmol) in DMF (3mL) was added HATU (209 mg, 0.55 mmol) at 0° C. After 20 minutes, thecrude solution of 1L (0.26 mmol) in 10 mL dioxane was added, followed byDIPEA (0.18 mL, 1.1 mmol). The resulting mixture was warmed to roomtemperature and stirred for 1 hour until LC-MS monitoring indicating thecompletion of reaction. The reaction mixture was concentrated to halfvolumn and diluted with EtOAc/hexanes (4/1, v/v). After washed with 0.1NHCl, water and brine, the organic layer was dried over Na₂SO₄. Afterconcentration, the residue was purified by column chromatography (ethylacetate/hexanes, v/v, 1/3˜1/1) to obtain the title compound 1M (85 mg)as slightly yellow solid.

MS calcd for (C₃₄H₄₆BNO₈S): 639MS (ESI, positive) found: (M+1): 640MS (ESI, negative) found: (M−1): 638

Step 13: Synthesis of Compound 1

To the mixture of 1M (85 mg, 0.13 mmol) and triethylsaline (155 mg, 1.3mmol) was added TFA (2 mL). The resulting solution was stirred at roomtemperature for 1.5 hours before it was concentrated to dryness. Theresidue was washed with hexanes twice and purified by prep-HPLC (C18,acetonitrile and water as mobile phases, 0.1% formic acid) to obtain thetitle compound T110 (16 mg) as white solid.

MS calcd for (C₁₅H₁₄BNO₅S): 331MS (ESI, positive) found: (M+1): 332MS (ESI, negative) found: (M−1): 330

¹H-NMR: (300 MHz, CDCl₃) δ 7.82 (dd, 1H), 7.31 (dd, 1H), 7.24 (dd, 1H),6.87 (d, 2H), 6.83 (t, 1H), 4.70 (m, 1H), 3.85 (s, 2H), 0.68-0.82 (m,2H). NMR:

Example 24-(5-AMINO-1,3,4-THIADIAZOLE-2-CARBOXAMIDO)-2-HYDROXY-3,4-DIHYDRO-2H-BENZO[E][1,2]OXABORININE-8-CARBOXYLICACID (2)

Step 1: Synthesis of Compound 1O

To the solution of 1K (200 mg, 0.31 mmol) in 10 mL dioxane was addedPd/C (110 mg, 10%) and HCl solution (0.16 mL, 4 N in dioxane, 0.62mmol). The resulting mixture was stirred at room temperature underhydrogen (1 atm) atmosphere for 2 hours. The reaction mixture wasfiltered through Celite and washed with dioxane.

To the solution of 5-(N-Boc-amino)-1,3,4-thiadiazole-2-carboxylic acid(114 mg, 0.46 mmol) in DMF (4 mL) was added HATU (190 mg, 0.5 mmol) at0° C. After 20 minutes, the above solution in 10 mL dioxane was added,followed by DIPEA (0.22 mL, 1.3 mmol). The resulting mixture was warmedto room temperature and stirred for 1 hour until LC-MS monitoringindicating the completion of reaction. The reaction mixture wasconcentrated to half volumn and diluted with EtOAc/hexanes (4/1, v/v).After washed with 0.1N HCl, water and brine, the organic layer was driedover Na₂SO₄. After concentration, the residue was purified by columnchromatography (ethyl acetate/hexanes, v/v, 1/3˜1/1) to obtain the titlecompound 10 (102 mg) as white solid.

MS calcd for (C₃₆H₅₁BN₄O₁₀S): 742MS (ESI, negative) found: (M−1): 741

Step 2: Synthesis of Compound 2

To the mixture of 10 (102 mg, 0.14 mmol) and triethylsaline (1 mL) wasadded TFA (4 mL) and isobutylboronic acid (35 mg, 0.34 mmol). Theresulting solution was stirred at room temperature 4 hours before it wasconcentrated to dryness. The residue was purified by prep-HPLC (C18,acetonitrile and water as mobile phases, 0.1% formic acid) to obtain thetitle compound T520 (8 mg) as white solid.

MS calcd for (C₁₂H₁₁BN₄O₅S): 334MS (ESI, positive) found: (M+1): 335MS (ESI, negative) found: (M−1): 333

¹H-NMR: (300 MHz, CDCl₃) δ 7.88 (dd, 1H), 7.48 (dd, 1H), 6.93 (t, 1H),4.80 (m, 1H), 1.05-1.35 (m, 2H).

Example 32-HYDROXY-4-(2-(METHYLTHIO)ACETAMIDO)-3,4-DIHYDRO-2H-BENZO[E][1,2]OXABORININE-8-CARBOXYLICACID (3)

Step 1: Synthesis of Compound 1N

To the solution of 1K (345 mg, 0.53 mmol) in 12 mL dioxane was addedPd/C (2000 mg, 10%) and HCl solution (0.27 mL, 4 N in dioxane, 1.1mmol). The resulting mixture was stirred at room temperature underhydrogen (1 atm) atmosphere for 2 hours. The reaction mixture wasfiltered through Celite and washed with dioxane.

To the solution of (methylthio)acetic acid (85 mg, 0.80 mmol) in DMF (5mL) was added HATU (323 mg, 0.85 mmol) at 0° C. After 20 minutes, theabove solution in 13 mL dioxane was added, followed by DIPEA (0.35 mL,2.1 mmol). The resulting mixture was warmed to room temperature andstirred for 1 hour until LC-MS monitoring indicating the completion ofreaction. The reaction mixture was concentrated to half volumn anddiluted with EtOAc/hexanes (4/1, v/v). After washed with 0.1N HCl, waterand brine, the organic layer was dried over Na₂SO₄. After concentration,the residue was purified by column chromatography (ethylacetate/hexanes, v/v, 1/3˜1/1) to obtain the title compound 1N (150 mg)as white solid.

MS calcd for (C₃₁H₄₆BNO₈S): 603MS (ESI, positive) found: (M+1): 604MS (ESI, negative) found: (M−1): 602

Step 2: Synthesis of Compound 3

To the mixture of 1N (150 mg, 0.25 mmol) and triethylsaline (150 mg) wasadded TFA (4 mL) and isobutylboronic acid (55 mg, 0.54 mmol). Theresulting solution was stirred at room temperature 4 hours before it wasconcentrated to dryness. The residue was purified by prep-HPLC (C18,acetonitrile and water as mobile phases, 0.1% formic acid) to obtain thetitle compound 3 (16 mg) as white solid.

MS calcd for (C₁₂H₁₄BNO₅S): 295MS (ESI, positive) found: (M+1): 296MS (ESI, negative) found: (M−1): 294

¹H-NMR: (300 MHz, CDCl₃) δ 7.92 (dd, 1H), 7.43 (dd, 1H), 6.94 (t, 1H),4.80 (m, 1H), 3.34 (s, 2H), 2.12 (s, 3H), 0.80-1.00 (m, 2H).

Example 44-(BENZYLSULFONYL)-2-HYDROXY-3,4-DIHYDRO-2H-BENZO[E][1,4,2]OXAZABORININE-8-CARBOXYLICACID (4)

Step 1: Synthesis of 4B

To a mixture of TFAA/TFA (20 mL/30 mL) was added compound 4A (4.4 g, 24mmol) at −4° C., followed by acetone (8 mL) dropwise over 30 mins. Thesolution was stirred at room temperature overnight and 30 hours at 90°C. The reaction mixture was diluted with DCM, washed with water andsaturated NaHCO₃(aq), dried over Na₂SO₄. After concentration, themixture was purified by silica gel chromatography to get the titlecompound 4B (4.1 g, 76% yield).

¹H NMR: (400 MHz, CDCl₃) δ 8.22-8.28 (m, 2H), 7.23-7.27 (m, 1H), 1.82(s, 6H).

Step 2: Synthesis of 4C

The mixture of compound 4B (4.1 g) and Pd/C (1 g, 10%) in methanol (100mL) was stirred under H₂ (1 atm) for 12 h at room temperature. Afterfiltration, the filtrate was evaporated to dryness, and purified bysilica gel chromatography to afford the title compound 4C (2.9 g, 81.7%yield).

¹H NMR: (400 MHz, CDCl₃) δ 7.33 (m, 1H), 6.88-6.95 (m, 2H), 3.83 (broads, 2H), 1.74 (s, 6H).

Step 3: Synthesis of 4D

To a solution of compound 4C (2.8 g, 14.5 mmol) and triethylamine (4.4g, 43.5 mmol) in DCM (30 mL) was added BnSO₂Cl (2.77 g, 14.5 mmol). Themixture was stirred at room temperature overnight before it wasevaporated to dryness. The residue was purified by silica gelchromatography to get the title compound 4D (1 g, 20% yield).

¹H NMR: (400 MHz, CDCl₃) δ 7.70-7.72 (m, 2H), 7.31-7.37 (m, 3H),7.23-7.26 (m, 2H), 7.06-7.09 (t, 1H), 6.58 (s, 1H), 4.39 (s, 2H), 1.69(s, 6H).

Step 4: Synthesis of 4F

To a solution of compound 4D (1 g, 2.88 mmol) and K₂CO₃ (1.19 g, 8.64mmol) in DMF was added compound 4E (1.18 g, 4.32 mmol) (WO2013/56163).The mixture was stirred at room temperature overnight before it wasevaporated to dryness. The residue was purified by silica gelchromatography to get the title compound 4F (0.5 g, 32% yield).

¹H NMR: (400 MHz, CDCl₃) δ 7.88-7.91 (m, 1H), 7.46-7.47 (m, 2H),7.32-7.37 (m, 4H,), 6.98-7.00 (m, 1H), 4.40 (s, 2H), 4.22 (dd, 1H), 3.31(s, 2H), 2.21-2.38 (m, 1H), 0.2.02-2.08 (m, 1H), 1.91-1.95 (m, 2H),1.79-1.80 (s, 6H), 1.31 (s, 3H), 1.28 (s, 3H), 0.79 (s, 3H), 0.73 (d,1H).

Step 5: Synthesis of 4

Compound 4F (500 mg) in HCl (6 mol/L, 2 mL) and 1,4-dioxane (2 mL) washeated to reflux (oil bath: 110° C.) for 3 hour before it wasconcentrated to dryness. The residue purified by prep-HPLC to afford 4(82 mg) as white solid. The compound was obtained as a mixture of cyclicand acyclic boronate.

¹H NMR: (400 MHz, CD₃OD) δ 7.42-7.43 (d, 1H, J=4 Hz), 7.41-7.42 (d, 1H,J=4 Hz), 7.40-7.41 (d, 1H, J=4 Hz), 7.39-7.40 (m, 5H), 7.33-7.34 (m,2H), 7.28-7.29 (m, 3H), 7.15-7.18 (m, 4H), 6.87-6.91 (m, 1H), 6.83-6.85(m, 1H), 5.49 (s, 1H), 4.5 (s, 2H), 4.24 (s, 1H), 3.42 (s, 1H), 3.16 (s,2H).

MS calcd for (C₁₅H₁₄BNO₆S): 347.2MS (ESI, positive) found: (M+1): 348

Example 5 2-HYDROXY-3,4-DIHYDRO-1,2-BENZOXABORININE-8-CARBOXYLIC ACID

Step 1: Synthesis of 5B

To the solution of [IrCl(cod)]2 (11.1 mg, 0.0165 mmol) and dppe (13 mg,0.033 mmol) in dichloromethane (1 mL) was added pinacolborane (0.095 mL,0.66 mmol) under N2 atmosphere. The resulting solution was added intocompound 5A (112 mg, 0.55 mmol) (WO 2014107535) in dichloromethane (2mL) and stirred at room temperature for 18 hours. Crude NMR showed goodconversion. The reaction mixture was concentrated and purified by columnchromatography (silica gel, EtOAc/Hexanes, v/v, 1/4) to give the titledcompound 5B (150 mg) as colorless oil.

Step 2: Synthesis of 5

To the solution of compound 5B (˜140 mg) in dioxane (5 mL) was added 6Naqueous HCl (5 mL). The resulting solution was stirred at 100° C. for1.5 hours before it was cooled down. The reaction mixture wasconcentrated and purified by C18 reverse-phase prep-HPLC (acetonitrileand water as mobile phases, 0.1% formic acid) to give titled compound 5(39 mg) as white solid.

MS calcd for (C₉H₉BO₄): 192MS (ESI, negative) found: (2M−1): 383

¹H NMR (300 MHz, CD₃OD) δ 7.68 (dd, 1H), 7.33 (dd, 1H), 6.79 (t, 1H),2.69 (t, 2H), 1.09 (t, 2H).

Example 6 DISODIUM;4,4-DIHYDROXY-5-OXA-8-AZA-4-BORANUIDABICYCLO[4.4.0]DECA-1(6),7,9-TRIENE-7-CARBOXYLATE

Step 1: Synthesis of 6B

To a solution of known compound 6A (7 g, 21.73 mmol, 1.0 eq,Tetrahedron, 2011, 67, 8757) in THF:MeOH:H₂O (2:2:1, 100 mL) was addedLiOH (1.37 g, 32.6 mmol, 1.5 eq) at room temperature. The mixture wasstirred at rt for 1.5 hours. The solvent was removed under reducedpressure. The residue was redissolved in water, adjusted pH to 1 with 1NHCl, and extracted with ethyl acetate. The organics were dried overNa₂SO4, and concentrated to yield residue, which was purified by columnchromatography (DCM:MeOH=10:1) to give compound 6B (4.85 g, 72%). H NMR(CD₃OD, 300 MHz): δ 8.21 (d, J=4.8 Hz, 1H), 7.88 (d, J=4.8 Hz, 1H),7.55-7.36 (m, 5H), 5.15 (s, 2H).

Step 2: Synthesis of 6C

To a solution of compound 6B (4.8 g, 15.58 mmol, 1.0 eq) in ^(t)BuOH(150 mL) was added DMAP (195 mg, 1.596 mmol, 0.1 eq) and Boc₂O (10.2 g,46.74 mmol, 3 eq). The mixture was stirred overnight at 60° C. Thesolvent was removed under reduced pressure, and the resulting residuewas purified by column chromatography (ethyl acetate:hexanes=1:3) togive compound 6C (4.9 g, 86%). H NMR (CDCl₃, 300 MHz): δ 8.23 (d, J=4.8Hz, 1H), 7.63 (d, J=5.1 Hz, 1H), 7.55-7.38 (m, 5H), 5.13 (s, 2H),1.58-1.57 (m, 9H).

Step 3: Synthesis of 6D

To a solution of compound 6C (4.9 g, 13.45 mmol, 1.0 eq) in isopropylalcohol (250 mL) was added PdCl₂ (dppf) (878 mg, 1.08 mmol, 0.08 eq),potassium vinyltrifluroborate (4.5 g, 33.59 mmol, 2.5 eq), andtriethylamine (2.04 g, 20.17 mmol, 1.5 eq). The mixture was purged withN₂ and stirred at 86° C. for 3 hours. The solvent was removed underreduced pressure, and the resulting residue was purified by columnchromatography (ethyl acetate:hexanes=1:3) to give compound 6D (3.77 g,90%). H NMR (CDCl₃, 300 MHz): δ 8.38 (d, 1H), 7.52-7.28 (m, 6H), 6.95(dd, 1H), 5.95 (dd, 1H), 5.56 (dd, 1H), 5.01 (s, 2H), 1.6-1.58 (m, 9H).

Step 3: Synthesis of 6E

To a solution of PinBH (1.86 g, 14.54 mmol, 1.2 eq), [IrCl(COD)]₂ (163mg, 0.263 mmol, 0.02 eq) and dppe (191 mg, 0.479 mmol, 0.04 eq) in DCM(100 mL) was added compound 6D (3.77 g, 12.11 mmol, 1.0 eq) in DCM (50mL). The mixture was purged with N₂ and stirred overnight at roomtemperature. After addition of MeOH (10 mL), the solvent was removedunder reduced pressure, and the resulting residue was purified by columnchromatography (ethyl acetate:hexanes=1:3) to give compound 6E (2.58 g,48%). H NMR (CDCl₃, 300 MHz): δ 8.36 (d, 1H), 7.51-7.29 (m, 6H), 5.03(s, 2H), 2.80 (t, 2H), 1.59 (s, 9H). 1.29-1.18 (m, 14H).

Step 4: Synthesis of 6F

To a solution of compound 6E (2.58 g, 5.87 mmol, 1.0 eq) in MeOH (100mL) was added Pd/C. The mixture was stirred overnioght at roomtemperature. The mixture was filtered through celite and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography (DCM:MeOH=10:1) to give impure compound 6F (˜1.5 g).

MS calcd for (C₁₂H₁₆BNO₄): 249MS (ESI, positive) found: (M+1): 250

Step 5: Synthesis of 6

Step 1: A solution of compound 6F (1.5 g, 6 mmol, 1.0 eq) in TFA (12 mL)and TES (3 mL) was stirred at rt for 1.5 h. The mixture wasconcentrated, and purified by C18 reverse-phase prep-HPLC (acetonitrileand water as mobile phases, 0.1% formic acid). After lyophilization, theobtained white solid was dissolved in MeCN/H₂O, and adjusted to pH about7.9 using 0.1N aqueous NaOH. After stirred at room temperatureovernight, the solution was concentrated, and re-purified by C₁₈reverse-phase prep-HPLC (acetonitrile and water as mobile phases,neutral) to give the desired 6 sodium salt as white solid.

MS calcd for (C₈H₈BNO₄): 193MS (ESI, positive) found: (M+1) 194; (M+1+H₂O) 212.

¹H NMR (300 MHz, D₂O): δ 7.59 (d, 1H), 7.08 (d, 1H), 2.55 (t, 2H), 0.48(t, 2H).

Example 7DISODIUM;4,4-DIHYDROXY-8-METHOXY-5-OXA-4-BORANUIDABICYCLO[4.4.0]DECA-1(6),7,9-TRIENE-7-CARBOXYLATE

Step 1: Synthesis of 7B

To a solution of 2, 6-dimethoxybenzoic acid (7A) (50 g, 0.275 mol) inCHCl₃ (1 L) at 0° C. was added dropwise bromine (14.4 mL, 0.263 mol).The reaction mixture was stirred at 25° C. for 30 hours, before it wasconcentrated to dryness. The residue was purified by columnchromatography (ethyl acetate/hexanes) to afford compound 7B (32.5 g,48%) as white solid.

Step 2: Synthesis of 7C

To the solution of compound 7B (32.5 g, 0.132 mol) in THF (200 mL) wasadded Boc₂O (114.7 g, 0.526 mol), DMAP (4.8 g, 0.04 mol) and tBuOH (400mL). The resulting solution was stirred at 60° C. for 6 hours before itwas concentrated in vacuo. The residue was quickly passed through asilica gel column (ethyl acetate/hexanes) to give the correspondingt-butyl ester. To the solution of this ester and Boc₂O (17 g, 0.078 mol)in DCM (300 mL) was added DMAP (475 mg, 3.89 mmol). The resultingreaction mixture was stirred at room temperature for 1 hour before itwas concentrated to dryness. The residue was purified by columnchromatography (ethyl acetate/hexanes) to afford compound 7C (52.1 g,98%) as white solid.

Step 3: Synthesis of 7D

To a mixture of Zn powder (20 g, 0.302 mol) and compound 7E (100 mg,0.37 mmol) in anhydrous THF (100 mL) was added DIBAL-H (2.45 mL, 6.05mmol, 1.5 M in toluene) at room temperature. The mixture was stirred atroom temperature for 5 min, then more compound 7E (33 g, 0.121 mol) inanhydrous THF (100 mL) was added dropwise into the mixture over 20 min.The reaction mixture was warmed up to 50° C. and stirred at thistemperature for 1 hour before it was settled down at room temperature.The top layer of clear solution was transferred into a mixture ofcompound 7C (20 g, 50 mmol) and Pd(t-Bu3P)2 (917 mg, 1.79 mmol) in THF(300 mL) at room temperature under N₂. After stirring at roomtemperature for 1 hour, the reaction mixture was concentrated, andpurified by column chromatography (ethyl acetate/hexanes) to affordcompound 7D (21 g, 81%) as light yellow solid.

Step 4: Synthesis of 7F

To a solution of dichloromethane (4.2 mL, 0.066 mol) in anhydrous THF(200 mL), was added dropwise n-butyllithium (2.5 M in hexane, 18.5 mL,0.046 mol) along the wall of the flask over 1 h at −100° C. (cooled withliquid nitrogen and methanol), while keeping the internal temperaturebelow −90° C. After the addition, the mixture was stirred at −100° C.for 30 min before slow addition of the solution of compound 7D (17 g,0.033 mol) in anhydrous THF (60 mL) over 1 h at −100° C. The reactionmixture was slowly warmed up to room temperature over a period of 6hours and stirred overnight. The solvent was evaporated and the residuewas purified by column chromatography (ethyl acetate/hexanes) to affordcompound 7F (16.5 g, 88%) as light yellow solid.

Step 5: Synthesis of 7G

To a solution of compound 7F (3.0 g, 5.3 mmol, 1.0 eq) (WO 2014107536)in anhydrous THF (60 mL) was added a solution of LiBHEt₃ in THF (1 M,13.27 mL, 13.3 mmol, 2.5 eq) over 20 min at −78° C. The mixture wasstirred at rt overnight. The solvent was removed under reduced pressure.The crude was purified by column chromatography (PE/EA=50:1 to 9:1) togive compound 7G (2.2 g, 78%). H NMR (CDCl₃, 400 MHz): δ 7.24 (d, J=8.8Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 4.28-4.23 (m, 1H), 3.79 (s, 3H), 2.60(m, 2H), 2.39-2.25 (m, 2H), 2.20-2.12 (m, 1H), 2.04-2.01 (m, 1H),1.95-1.88 (m, 1H), 1.85-1.75 (m, 1H), 1.57 (s, 9H), 1.53 (s, 9H), 1.35(s, 3H), 1.27 (s, 3H), 1.11-1.02 (m, J=7.6 Hz, 2H), 0.83 (s, 3H).

Step 6: Synthesis of 7

To a mixture of compound 7G (2.0 g, 3.77 mmol, 1.0 eq), i-BuB(OH)₂ (499mg, 3.77 mmol, 1.3 eq) in hexane (20 mL) and methanol (20 mL) was added1 mL of hydrochloric acid at 0° C. The reaction mixture was stirred atrt overnight. The methanol layer was concentrated to give crude product(1.7 g).

The crude product (1.7 g) was then dissolved in dichloromethane (7 mL)and TFA (7 mL) was added slowly at 0° C. The reaction was stirred at rtfor 1 h. The mixture was concentrated and the residue was diluted withmethanol (3 mL) and water (3 mL). The mixture was then adjusted to pH 12with 0.1N aqueous solution of NaOH and stirred at rt overnight. Thesolid was filtered, washed with acetonitrile-water and dried to afford 7(650 mg, 71%) as a white solid.

MS calcd for (C₁₀H₁₁BO₅): 222MS (ESI, positive) found: (M+1) 223

H NMR (CD₃OD, 400 MHz): δ 6.71 (d, J=8.0 Hz, 1H), 6.18 (d, J=8.4 Hz,1H), 3.70 (s, 3H), 2.55 (t, J=6.8 Hz, 2H), 0.43 (t, J=7.2 Hz, 2H).

Example 8 DISODIUM;8-FLUORO-4,4-DIHYDROXY-5-OXA-4-BORANUIDABICYCLO[4.4.0]DECA-1(6),7,9-TRIENE-7-CARBOXYLATE

Step 1: Synthesis of 8B

The synthesis of the compound 8A can be found in WO 2014107536, which isincorporated herein by reference in its entirety. To a solution ofcompound 8A (3.0 g, 5.4 mmol, 1.0 eq) in anhydrous THF (80 mL) was addeda solution of LiBHEt₃ in THF (1 M, 13.6 mL, 13.6 mmol, 2.5 eq) over 20min at −78° C. The reaction was stirred at rt overnight and the solventwas removed under reduced pressure. The residue was purified by columnchromatography (PE/EA=10:1) to give compound 8B (2.0 g, 71%). ¹H NMR(CDCl₃, 400 MHz): δ 7.32-7.26 (m, 1H), 6.92 (t, J=8.8 Hz, 1H), 4.25 (dd,J=8.8 Hz, 1.6 Hz, 1H), 2.65 (dd, J=8.4 Hz, 2H), 2.31-2.28 (m, 1H),2.19-2.15 (m, 1H), 2.02 (t, J=5.6 Hz, 1H), 1.90-1.88 (m, 1H), 1.83-1.78(m, 1H), 1.59 (s, 9H), 1.54 (s, 9H), 1.35 (s, 3H), 1.28 (s, 3H), 1.11(dd, J=8.4 Hz, 2H), 1.03 (d, J=10.4 Hz, 1H), 0.83 (s, 3H).

Step 2: Synthesis of 8

A solution of compound 8B (2.0 g, 3.86 mmol, 1.0 eq) in 90% TFA (12 mL)and TES (4 mL) was stirred at rt for 1 h. The mixture was concentratedto give the crude product (1.5 g) which was used directly in next stepwithout purification.

To a solution of the crude product (1.5 g) in dioxane (5 mL) andhydrochloric acid (5 mL) was added i-BuB(OH)₂ (590 mg, 5.79 mmol, 1.5eq). The mixture was stirred at rt for 1 h. The solvent was removedunder reduced pressure. The mixture was then adjusted to pH 12 with 0.1N aqueous solution of NaOH and was stirred at rt for 48 h. The mixturewas then purified by prep-HPLC to give 8 (370 mg, 41%) as white solid.

MS calcd for (C₉H₈BFO₄): 210MS (ESI, positive) found: (M+1) 211

¹H NMR (D₂0, 400 MHz): δ 6.93 (m, 1H), 6.40 (m, J=8.8 Hz, 1H), 2.60 (t,J=6.4 Hz, 2H), 0.40 (t, J=7.2 Hz, 2H).

Example 9Disodium;(3S)-4,4-dihydroxy-3-methyl-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 9B

To a solution of compound 9A (US2014/194381) (1.1 g, 2.06 mmol, 1.0 eq)in anhydrous THF (10 mL) was added dropwise a solution of methylmagnesium bromide in THF (3 M, 1.03 mL, 3.1 mmol, 1.5 eq) over 5 min at−78° C. The reaction mixture was slowly warmed up to room temperature in18 h before it was quenched with saturated aq NH₄Cl. The organic layerwas concentrated and the residue was purified by column chromatography(PE/EA=10:1) to give compound 9B (0.9 g, 81%).

Step 2: Synthesis of 9

To a solution of compound 9B (0.5 g) in dioxane (2 mL) and concentratedHCl (2 mL) was added i-BuB(OH)₂ (184 mg, 1.83 mmol, 2 eq) at roomtemperature. The mixture was stirred at rt for 3 h. The reaction mixturewas concentrated in vacuo, and the residue was dissolved in H₂O/MeCN.The resulting solution was adjusted to pH=12 and purified by prep-HPLC(C18, neutral) to give 9 (18 mg, 9%) as white solid.

MS calcd for (C₁₀H₁₁BO₄): 206MS (ESI, positive) found: (M+1): 207

¹H NMR (CD₃OD, 400 MHz): δ 7.643-7.659 (d, J=6.4, 1 H), 7.158-7.303 (dd,J=7.6, 1 H), 6.710-6.883 (m, 1H), 2.598-2.758 (m, 2H), 1.255-1.295 (m,3H), 0.796-0.885 (m, 1H).

Example 10Disodium;(3R)-4,4-dihydroxy-3-methyl-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 10B

To a solution of compound 10A (prepared as 9A using (−)-Pinanediol) (2g, 3.74 mmol, 1.0 eq) in anhydrous THF (20 mL) was added dropwise asolution of methyl magnesium bromide in THF (3 M, 1.87 mL, 5.61 mmol,1.5 eq) over 10 min at −78° C. The reacion mixture was slowly warmed upto room temperature in 18 hours before it was quenched with saturatedNH₄Cl. The organic layer was concentrated and the residue was purifiedby column chromatography (PE/EA=10:1) to give compound 10B (1.3 g, 66%).

Step 2: Synthesis of 10

To a solution of compound 10B (1.3 g) in dioxane (6 mL) and hydrochloricacid (6 mL) was added i-BuB(OH)₂ (516 mg, 5.05 mmol, 2 eq) at roomtemperature. The mixture was stirred at rt for 3 hours. The reactionmixture was concentrated in vacuo, and the residue was dissolved inH₂O/MeCN. The resulting solution was adjusted to pH=12 and purified byprep-HPLC (C18, neutral conditions) to give 10 (295 mg, 51%) as whitesolid.

MS calcd for (C₁₀H₁₁BO₄): 206MS (ESI, positive) found: (M+1): 207

¹H NMR (CD₃OD, 400 MHz): δ 7.564 (s, 1H), 7.064-7.078 (d, J=5.6, 1 H),6.606-6.644 (d, J=15.2, 1 H), 2.807-2.854 (m, 1H), 2.397-2.450 (m, 1H),0.789-0.875 (m, 4H).

Example 11 Disodium;(3S)-4,4-dihydroxy-8-methoxy-3-methyl-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 11A

To a solution of compound 7F (1.1 g, 1.95 mmol, 1.0 eq) in anhydrous THF(10 mL) was added dropwise a solution of methyl magnesium bromide in THF(3 M, 0.98 mL, 2.93 mmol, 1.5 eq) over 5 min at −78° C. The reactionmixture was slowly warmed up to room temperature in 18 hours before itwas quenched with saturated NH₄Cl. The organic layer was concentratedand the residue was purified by column chromatography (PE/EA=10:1) togive compound 11A (0.9 g, 81%).

Step 2: Synthesis of 11

To a solution of compound 11A (0.45 g) in dioxane (3 mL) andhydrochloric acid (3 mL) was added i-BuB(OH)₂ (169 mg, 1.65 mmol, 2 eq)at room temperature. The mixture was stirred at rt for 3 hours. Thereaction mixture was concentrated in vacuo, and the residue wasdissolved in H₂O/MeCN. The resulting solution was adjusted to pH=12 andpurified by prep-HPLC (C18, neutral) to give 11 (75 mg, 38%) as whitesolid.

ESI-MS: [M+H]⁺: 237

H NMR (CD₃OD, 400 MHz): δ 6.747-6.767 (d, J=8, 1 H), 6.226-6.247 (dd,J=8.4, 1 H), 3.676-3.711 (m, 3H), 2.618-2.653 (m, 1H), 2.285-2.340 (m,1H), 0.805-0.822 (m, 3H), 0.722-0.725 (m, 1H).

Example 12Disodium;(3R)-4,4-dihydroxy-3-(2-hydroxyethyl)-8-methoxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 12A

To a solution of compound 7F (5 g, 8.85 mmol, 1.0 eq) in anhydrous THF(50 mL) was added allylmagnesium bromide (11.5 mL, 1 M in THF, 11.5mmol, 1.3 eq) dropwise over 10 minutes at −78° C. The reaction mixturewas slowly warmed up to room temperature in 18 hours before it wasquenched with saturated NH₄Cl. The organic layer was concentrated andthe residue was purified by column chromatography (PE/EA=10:1) to givecompound 12A (4.5 g, 89%).

Step 2: Synthesis of 12B

To a solution of compound 12A (730 mg, 1.28 mmol, 1.0 eq) in DCM (30 mL)was bubbled with O₃ at −78° C. until the solution turned to slightlyblue. The nitrogen was bubbled in to remove the color. The colorlesssolution was added dimethylsulfide (3 mL) and slowly warmed up to roomtemperature in 6 hours. The solvent was removed under reduced pressureand the residue was purified by column chromatography (PE/EA=3:1) togive compound 12B (400 mg, 55%).

Step 3: Synthesis of 12C

To a solution of compound 12B (400 mg, 0.69 mmol, 1.0 eq) in anhydrousTHF (50 mL) was added NaBH₄ (31 mg, 0.83 mmol, 1.2 eq) at 0° C. Themixture was stirred at room temperature for 1 hour before it wasconcentrated under reduced pressure. The residue was purified by columnchromatography (PE/EA=1:1) to give compound 12C (180 mg, 45%).

Step 4: Synthesis of 12

To a solution of compound 12C (180 mg) in dioxane (3 mL) andhydrochloric acid (3 mL) was added i-BuB(OH)₂ (64 mg, 0.63 mmol, 2 eq).The mixture was stirred at rt for 3 hours. The reaction mixture wasconcentrated in vacuo, and the residue was dissolved in H₂O/MeCN. Theresulting solution was adjusted to pH=12 and purified by prep-HPLC (C18,neutral) to give 12 (9 mg, 10%) as white solid.

ESI-MS: [M+H]⁺: 267

¹H NMR (CD₃OD, 400 MHz): δ 6.735-6.754 (d, J=7.6, 1 H), 6.214-6.235 (dd,J=8.4, 1 H), 3.701 (s, 3H), 3.607-3.685 (m, 2H), 2.518-2.553 (m, 1H),2.485-2.496 (m, 1H), 1.758-1.823 (m, 1H), 1.458-1.495 (m, 1H),1.005-1.012 (m, 1H).

Example 13Disodium;4,4-dihydroxy-8-(triazol-1-yl)-5-oxa-4-boranuidabicyclo[4.4.0]deca-(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 13B

To a solution of 13A (142.2 g, 497 mmol, 1.0 eq) in dry THF (350 mL) wasadded LDA (freshly made, 544 mmol, 1.1 eq) at −78° C. The mixture wasslowly warmed up to room temperature for 12 hours under nitrogenatmosphere. The mixture was concentrated and the residue was partitionedin EA and water. The aqueous layer was adjusted to PH=6 with 1N HCl. Theorganic layer was washed with brine, dried over Na₂SO₄ and thenconcentrated under reduced pressure to give 13B (142.6 g, 98%).

Step 2: Synthesis of 13C

To a solution of 13B (45 g, 156 mmol, 1.0 eq) in EtOH/H₂O (200 mL, 7/3,v/v) was added NaN₃ (20.5 g, 3.15 mol, 2.0 eq), CuI (3 g, 157 mmol, 0.1eq), N1,N2-dimethylethane-1,2-diamine (2.1 g, 23.8 mmol, 0.15 eq) andSodium L-ascorbate (1.55 g, 7.82 mmol, 0.08 eq). The mixture was stirredat 80° C. for 2 hours under nitrogen atmosphere. The mixture was cooledto room temperature and quenched with 0.2 N HCl. The resulting mixturewas extracted with EA (2×) and the organic layer was washed with water,brine. The solvent was removed in vacuo and the residue was purified bycolumn chromatography on silica gel (PE:EA=100:1 to 30:1) to give 13C(25.8 g, 66%).

Step 3: Synthesis of 13D

To a solution of 13C (23 g, 92.4 mmol, 1.0 eq) in dry THF (250 mL) wasadded Boc₂O (26.2 g, 120.1 mmol, 1.3 eq), DMAP (1.13 g, 9.24 mmol, 0.1eq) and TEA (10.3 g, 101.6 mmol, 1.1 eq). The mixture was stirred atroom temperature for 12 hours. The reaction was monitored by TLC. Themixture was concentrated and the residue was purified by columnchromatography on silica gel (PE:EA=1:0-100:1) to give 13D (32.2 g,86%).

Step 4: Synthesis of 13E

To a solution of 13D (20.1 g, 57.6 mmol, 1.0 eq) in CCl₄ (300 mL) wasadded NBS (11.3 g, 63.4 mmol, 1.1 eq) and BPO (2.8 g, 11.5 mmol, 0.2eq). The mixture was stirred at 100° C. for 12 hours under nitrogenatmosphere. The reaction was monitored by TLC. The mixture wasconcentrated and the residue was purified by column chromatography onsilica gel (PE:EA=300:1 to 20:1) to give 13E (18 g, 79%).

Step 5: Synthesis of 13F

To a solution of 13E (18.3 g, 42.7 mmol, 1.0 eq) in dioxane (550 mL) wasadded diboron reagent (18.4 g, 51.2 mmol, 1.2 eq), KOAc (8.4 g, 85.5mmol, 2.0 eq) and PdCl₂ (dppf) (1.7 g, 2.1 mmol, 0.05 eq). The mixturewas stirred at 70° C. for 12 hours under nitrogen atmosphere. Thereaction was monitored by TLC. The resulting mixture was filtered andthe filtrate was concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel (PE:EA=20:1 to 10:1) togive 13F (8 g, 36%).

ESI-MS: [M+H]⁺: 528

Step 6: Synthesis of 13G

To a solution of 13F (6 g, 11.39 mmol, 1.0 eq) in dry THF (120 mL) wasadded CH₂ICl (4.02 g, 22.77 mmol, 2.0 eq), followed by slow addition ofn-BuLi (7.75 ml, 19.35 mmol, 1.7 eq) at −78° C. in 20 minutes undernitrogen atmosphere. The mixture was slowly warmed up to 0° C. in 12hours. The reaction was monitored by TLC. The mixture was concentratedand the residue was purified by column chromatography on silica gel(PE:EA=200:1 to 10:1) to give 13G (3.67 g, 60%).

Step 7: Synthesis of 13H

A mixture of 13G (500 mg, 0.92 mmol, 1.0 eq), TMS-acetylene (2.27 g,23.1 mmol, 25.0 eq), CuI (529 mg, 2.77 mmol, 3.0 eq) and DIPEA (1.08 g,8.36 mmol, 9.0 eq) in THF (5 mL) was stirred at 80° C. for 12 hoursunder nitrogen atmosphere. The reaction was monitored by TLC. Theresulting mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel (PE:EA=100:1 to 5:1) to give 13H (410 mg, 70%).

Step 8: Synthesis of 13I

To a solution of 13H (360 mg, 0.56 mmol, 1.0 eq) in THF (12 mL) wasadded TBAF (2.8 mL, 1M in THF, 2.8 mmol, 5.0 eq) under nitrogenatmosphere. After 2 hours at 50° C. reaction mixture was cooled down andconcentrated. The residue was purified by column chromatography onsilica gel (PE:EA=50:1 to 2:1) to give 13I (260 mg, 81%).

Step 9: Synthesis of 13

To the solution of 13I (50 mg, 0.08 mmol, 1.0 eq) in dioxane (1 mL) wasadded i-BuB(OH)₂ (23 mg, 0.22 mmol, 2.5 eq) and concentrated HCl (1 mL).The reaction mixture was stirred at rt for 1 hour. The reaction mixturewas concentrated in vacuo, and the residue was dissolved in H₂O/MeCN.The resulting solution was adjusted to pH=12 and purified by prep-HPLC(C18, neutral) to give 13 (10.4 mg, 46%) as white solid.

ESI-MS: [M+H]⁺: 260

¹H NMR (400 MHz, D₂O): δ 8.14 (s, 1H), 7.88 (s, 1H), 7.17 (d, J=8.8 Hz,1H), 6.80 (d, J=7.6 Hz, 1H), 2.78-2.74 (m, 2H), 0.54 (d, J=7.2 Hz, 2H).

Example 14Disodium;8-[4-(2-aminoethyl)triazol-1-yl]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 14A

To a solution of compound 13G (220 mg, 0.37 mmol, 1.0 eq) in THF (5 mL)was added tert-butyl but-3-yn-1-ylcarbamate (375 mg, 2.22 mmol, 6.0 eq),CuI (141 mg, 0.74 mmol, 2.0 eq) and DIPEA (287 mg, 2.22 mmol, 6.0 eq).The mixture was stirred at 60° C. for 12 hours under nitrogenatmosphere. The reaction was monitored by TLC. The mixture was filteredand concentrated. The residue was purified by column chromatography onsilica gel (PE/EA=10:1 to 2:1) to give compound 14A (195 mg, 70%).

Step 2: Synthesis of 14

To the solution of 14A (250 mg, 0.35 mmol, 1.0 eq) in dioxane (3 mL) wasadded i-BuB(OH)₂ (90 mg, 0.88 mmol, 2.5 eq) and concentrated HCl (3 mL).The reaction mixture was stirred at rt for 1 hour. The reaction mixturewas concentrated in vacuo, and the residue was dissolved in H₂O/MeCN.The resulting solution was adjusted to pH=12 and purified by prep-HPLC(C18, neutral) to give 14 (10.4 mg, 46%) as white solid.

ESI-MS: [M+H]⁺: 303

¹H NMR (400 MHz, D₂O): δ 8.03 (s, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.76 (d,J=7.6 Hz, 1H), 3.41-3.37 (m, 2H), 3.19-3.13 (m, 2H), 2.73 (d, J=6.0 Hz,2H), 0.47 (d, J=5.2 Hz, 2H).

Example 15Disodium;4,4-dihydroxy-8-(1H-pyrazol-5-yl)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 15B

To the solution of compound 15A (298 g, 1.93 mol, 1.0 eq) and DIA (98 g,0.97 mol, 0.5 eq) in DCM (3.5 L) was added NBS (362 g, 2.03 mol, 1.05eq) in small portions at −78° C. The mixture was slowly warmed to roomtemperature and stirred for 16 h as TLC monitoring showed the completionof reaction. The raction mixture was evaporated to dryness, and theresidue was stirred in 1 N HCl (2 L) 0.5 hour. The precipitate wasfiltrated to give compound 15B (370 g, 83%) as light yellow solid.

Step 2: Synthesis of 15C

A solution of compound 15B (370 g, 1.59 mol, 1.0 eq) in t-BuOH/THF (800mL/1600 mL) was stirred at 55° C. for 10 minutes before Boc₂O (1750 g,8.03 mol, 5.05 eq) and DMAP (155.2 g, 1.27 mol, 0.8 eq) were added insmall portions. The mixture was stirred at 55° C. until compound 15B wasfully consumed. The mixture was cooled to room temperature and moreBoc₂O (693 g, 3.18 mol, 2 eq) and DMAP (155.2 g, 1.27 mol, 0.8 eq) wereadded. After 18 hours, the reaction mixture was concentrated to drynessin vacuo, purified by column chromatography to give compound 15C (700 g,90%).

Step 3: Synthesis of 15D

The mixture of compound 15C (230 g, 0.47 mol, 1.0 eq), potassiumvinyltrifluoroborate (126 g, 0.94 mol, 2.0 eq), TEA (143 g, 1.42 mol,3.0 eq) and PdCl₂ (dppf)₂ (20 g, 23.5 mmol, 0.05 eq) in dioxane (3.0 L)was stirred at 90° C. for 72 hours under N₂ atmosphere. Completion ofthe reaction was monitored by NMR. The mixture was concentrated andpurified by column chromatography (eluted with PE) to give compound 15D(94 g, 46%).

Step 4: Synthesis of 15E

The mixture of compound 15D (94 g, 215.6 mmol, 1.0 eq),Bis(pinacolato)diboron (82 g, 323.4 mmol, 1.5 eq), Cu₂O (1.54 g, 10.8mmol, 0.05 eq), K₂HPO₃ (56.3 g, 323.4 mmol, 1.5 eq) and PPh₃ (2.82 g,10.8 mmol, 0.05) in MeOH (1.2 L) was stirred at 50° C. for 16 hours. Thereaction was monitored by HNMR. The reaction mixture was filtered, andthe filtrated was concentrated in vacuo. The residue was purified byflash chromatography to give compound 15E (88.5 g, 73%).

ESI-MS: [M+H]⁺: 565

Step 5: Synthesis of 15F

The mixture of compound 15E (88.5 g, 157 mmol, 1.0 eq) and(+)-pinanediol (69.5 g, 0.409 mol, 2.61 eq) in THF (500 mL) was stirredat room temperature for 72 hours. The reaction mixture was concentratedin vacuo and the residue was purified by flash chromatography to givecompound 15F (90 g, 100%).

ESI-MS: [M+H]⁺: 617

Step 6: Synthesis of 15G

A solution of compound 15F (100.6 g, 0.163 mol, 1.0 eq) in THF (500 mL)was added pyrrolidine (11.6 g, 14 mL, 0.163 mmol, 1.0 eq) at roomtemperature. The reaction mixture was stirred at 35° C. for 3 hoursbefore it was concentrated in vacuo. The residue was purified by flashchromatography to give compound 15G (90 g, 98%). ESI-MS: [M+H]⁺: 517

Step 7: Synthesis of 15H

To a solution of compound 15G (8.2 g, 15.9 mol, 1.0 eq) in DCM (50 mL)was added TEA (2.1 g, 20.8 mmol, 1.3 eq), followed by Tf₂O (4.7 g, 16.7mmol, 1.05 eq) dropwise at −78° C. The mixture was warmed to roomtemperature and stirred for 16 hours, LC-MS indicating the completion ofreaction. The reaction solution was concentrated in vacuo, and theresidue was stirred in 200 mL PE at room temperature for 0.5 hour. Thenthe solid was filtered off, and the PE layer was concentrated to givecrude compound 15H (7.43 g, 72%) as yellow oil.

ESI-MS: [M+H]⁺: 649

Step 8: Synthesis of 15I

The mixture of 3-pyrazoleboronic acid (155 mg, 1.39 mmol, 1.5 eq), CuCl₂(9 mg, 0.091 mmol, 0.1 eq) and ZnCl₂ (126 mg, 0.926 mmol, 1.0 eq) in DMF(5 mL) was degassed and stirred at room temperature for 20 minutes. ThenCs₂CO₃ (603 mg, 1.85 mmol, 2.0 eq) and compound 15H (600 mg, 0.926 mmol,1.0 eq) were added in sequence. The mixture was stirred for another 20minutes before PdCl₂ (dppf)₂ (38 mg, 0.047 mmol, 0.05 eq) was added. Thereaction mixture was degassed again and stirred at 85° C. for 20 hours.The reaction was monitored by LC-MS. After filtration through a shortcelite pad, the filtrate was concentrated and purified by flashchromatography (PE:EA=20:1 to 1:1) to give compound 15I (136 mg, 26%).

ESI-MS: [M+H]⁺: 567

Step 9: Synthesis of 15

To the solution of compound 15I (50 mg, 0.088 mmol, 1.0 eq) in dioxane(1 mL) was added i-BuB(OH)₂ (23 mg, 0.226 mmol, 2.5 eq), followed byconcentrated HCl (1 mL). The reaction mixture was stirred at roomtemperature for 16 hours. The reaction was monitored by LC-MS. Thereaction mixture was concentrated in vacuo, and the residue wasdissolved in H₂O/MeOH. The resulting solution was adjusted to pH=12 andpurified by prep-HPLC (C18, neutral) to give 15 (9.0 mg, 35%) as whitesolid.

LC-MS: [M+1]=259

¹H NMR (400 MHz, D₂O): δ 7.67 (s, 1H), 7.11 (d, J=7.6 Hz, 1H), 6.99 (d,J=6.4 Hz, 1H), 6.59 (s, 1H), 2.76-2.72 (m, 2H), 0.71 (m, 2H).

Example 16Disodium;4,4-dihydroxy-8-(1H-triazol-5-yl)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 16A

The solution of compound 15H (1 g, 1.54 mmol, 1.0 eq),ethynyltrimethylsilane (300 mg, 3.085 mmol, 2.0 eq), CuI (14.7 mg, 0.077mmol, 0.05 eq), Pd(dppf)Cl₂ (63 mg, 0.077 mmol, 0.05 eq) and TEA (467mg, 4.6 mmol, 3.0 eq) in dioxane (15 mL) was refluxed for 5 hours undernitrogen atmosphere. The reaction was monitored by TLC. The reactionmixture was concentrated and the residue was purified by flashchromatography to give compound 16A (600 mg, 70%) as yellow oil.

Step 2: Synthesis of 16B

To the solution of compound 16A (240 mg, 0.40 mmol, 1.0 eq) in THF (2mL) was added TBAF (0.80 mL, 1M in THF, 0.80 mmol, 2.0 eq). Theresulting solution was stirred at 35° C. for 16 hours. The reactionmixture was diluted with EA and washed with water and brine. The organiclayer was concentrated to give crude compound 16B (180 mg, 85%) whichwas used directly for the next step.

Step 3: Synthesis of 16C

The mixture of compound 16B (180 mg, 0.34 mmol, 1.0 eq), TMS-N₃ (1.18 g,10.2 mmol, 30 eq) and CuI (195 mg, 1.02 mmol, 3.0 eq) in dioxane (2 mL)was stirred at 80° C. for 16 hours under nitrogen atmosphere. Thereaction was monitored by LC-MS. After cooled to room temperature, thereaction mixture was filtrated through silica gel pad and washed withEA. The filtrate was concentrated to give crude compound 16C (200 mg,91%) which was used directly for the next step.

Step 4: Synthesis of 16D

To the solution of compound 16C (200 mg, 0.31 mmol, 1.0 eq) in THF (2mL) was added TBAF (0.62 mL, 1 M in THF, 0.62 mmol, 2.0 eq). Theresulting solution was stirred at 35° C. for 16 hours. The reactionmixture was monitored by LC-MS. The reaction mixture was diluted with EAand washed with water and brine. The organic layer was concentrated togive crude compound 16D (150 mg, 85%) which was used directly for nextstep.

Step 5: Synthesis of 16

To the solution of 16D (150 mg, 0.26 mmol, 1.0 eq) in dioxane (3 mL) wasadded i-BuB(OH)₂ (54 mg, 0.53 mmol, 2.0 eq) and concentrated HCl (3 mL).The reaction mixture was stirred at rt for 16 hours. The reactionmixture was concentrated in vacuo, and the residue was dissolved inH₂O/MeOH. The resulting solution was adjusted to pH=12 and purified byprep-HPLC (C18, neutral) to give 16 (33 mg, 48%) as white solid.

ESI-MS: [M+H]⁺: 260

¹H NMR (400 MHz, CD₃OD): δ 8.01-7.99 (m, 1H), 7.02-6.98 (m, 2H),2.72-2.65 (m, 2H), 1.31-1.25 (m, 2H).

Example 17Disodium;8-[1-(2-aminoethyl)triazol-4-yl]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 17A

A mixture of compound 16B (180 mg, 0.34 mmol, 1.0 eq),N-Boc-2-azido-ethylamine (127 mg, 0.68 mmol, 2.0 eq) and CuI (65 mg,0.34 mmol, 1.0 eq) in dioxane (2 mL) was stirred at 80° C. for 4 hoursunder nitrogen atmosphere. The reaction was monitored by LC-MS. Aftercooled to room temperature, the reaction mixture was filtrated throughsilica gel pad and washed with EA. The filtrate was concentrated to givecrude compound 17A (200 mg, 82%) which was used directly for the nextstep.

ESI-MS: [M+H]⁺: 711

Step 2: Synthesis of 17

To the solution of 17A (200 mg, 0.28 mmol, 1.0 eq) in dioxane (3 mL) wasadded i-BuB(OH)₂ (62 mg, 0.56 mmol, 2.0 eq) and concentrated HCl (3 mL).The reaction mixture was stirred at rt for 16 hours. The reactionmixture was concentrated in vacuo, and the residue was dissolved inH₂O/MeOH. The resulting solution was adjusted to pH=12 and purified byprep-HPLC (C18, neutral) to give 17 (31 mg, 36%) as white solid.

ESI-MS: [M+H]⁺: 303

¹H NMR (400 MHz, CD₃OD): δ 8.12 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.94(d, J=8.0 Hz, 1H), 4.50-4.46 (m, 2H), 3.40 (d, J=1.2 Hz, 1H), 3.21-3.19(m, 1H), 2.71-2.67 (m, 2H), 0.63 (d, J=6.4 Hz, 2H).

Example 18Disodium;8-ethynyl-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

To the solution of 16B (140 mg, 0.27 mmol, 1.0 eq) in dioxane (3 mL) wasadded i-BuB(OH)₂ (58 mg, 0.54 mmol, 2.0 eq) and concentrated HCl (3 mL).The reaction mixture was stirred at rt for 16 hours. The reactionmixture was concentrated in vacuo, and the residue was dissolved inH₂O/MeOH. The resulting solution was adjusted to pH=12 and purified byprep-HPLC (C18, neutral) to give 18 (8 mg, 13%) as white solid.

ESI-MS: [M+H]⁺: 217

¹H NMR (400 MHz, CD₃OD): δ 6.99 (d, J=7.6 Hz, 1H), 6.87 (d, J=7.6 Hz,1H), 2.68-2.64 (m, 2H), 2.51 (s, 1H), 0.47-0.42 (m, 2H).

Example 19Disodium;8-(azetidin-3-ylsulfanylmethyl)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 19A

To a solution of 15H (7.0 g, 10.8 mmol, 1.0 eq) in dioxane (100 mL) wasadded CH₂CHBF₃K (7.74 g, 12.96 mmol, 1.2 eq), PdCl₂ (dppf) (790 mg, 1.08mmol, 0.1 eq) and TEA (3.72 g, 32.4 mmol, 3.0 eq). The mixture wasflushed with nitrogen and stirred at 100° C. for 12 hours. The resultingmixture was cooled down to room temperature and filtered. The filtratedwas concentrated and the residue was purified by column chromatographyon silica gel (PE/EA=10:1) to give 19A (4 g, 62%) as yellow oil.

Step 2: Synthesis of 19B

A solution of 19A (3 g, 5.7 mmol, 1.0 eq) in dichloromethane (30 mL) wasbubbled with O₃ at −78° C. until the color of the solution turned tolight blue. Nitrogen gas was then bubbled and Me₂S (5 mL) was added. Thesolution was slowly warmed up to room temperature over 8 h and wasconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (PE/EA=10:1) to give 19B (1.7 g, 45%) asyellow solid.

Step 3: Synthesis of 19C

To a solution of 19B (1.7 g, 3.21 mmol, 1.0 eq) in THF (15 mL) was addedNaBH(OAc)₃ (1.7 g, 8 mmol, 2.5 eq) at 0° C. The mixture slowly warmed upto room temperature in 2 hours before it was concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (PE/EA=5:1)to give 19C (1.2 g, 86%) as yellow solid.

Step 4: Synthesis of 19D

To a solution of 19C (1.2 g, 2.26 mmol, 1.0 eq) in DCM (20 mL) was addedCBr4 (1.1 g, 3.39 mmol, 1.5 eq) and PPh₃ (8.9 mg, 3.39 mmol, 1.5 eq).The mixture was stirred at room temperature for 2 hours and wasconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (PE/EA=5:1) to give 19D (450 mg, 48%) as yellow solid.

Step 5: Synthesis of 19E

To a solution of 19D (150 mg, 0.25 mmol, 1.0 eq) in DCM (5 mL) was added1-Boc-3-mercapto-azetidine (52 mg, 0.27 mmol, 1.1 eq) and TEA (50.6 mg,0.5 mmol, 2.0 eq). The mixture was stirred at room temperature for 1hour. The reaction mixture was concentrated in vacuo and the residue waspurified by prep-TLC (PE/EA=4:1) to give 19E (120 mg, 83%) as yellowsolid.

Step 6: Synthesis of 19

To the solution of 19E (120 mg, 0.17 mmol, 1.0 eq) in dioxane (2 mL) wasadded i-BuB(OH)₂ (35 mg, 0.34 mmol, 2.0 eq) and concentrated HCl (2 mL).The reaction mixture was stirred at rt for 2 hours. The reaction mixturewas concentrated in vacuo, and the residue was dissolved in H₂O/MeCN.The resulting solution was adjusted to pH=12 and purified by prep-HPLC(C18, neutral) to give 19 (11 mg, 21%) as white solid.

ESI-MS: [M+H]⁺: 294

¹H NMR (400 MHz, CD₃OD/D₂O): δ 6.78 (d, J=7.6 Hz, 1H), 6.57 (d, J=7.2Hz, 1H), 3.92 (s, 2H), 3.80 (s, 2H), 3.69-3.67 (m, 1H), 3.60-3.58 (m,2H), 2.52-2.50 (m, 2H), 0.4-0.38 (m, 2H).

Example 20Disodium;4,4-dihydroxy-8-(1,3,4-thiadiazol-2-ylsulfanylmethyl)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 20A

To a solution of 19D (180 mg, 0.3 mmol, 1.0 eq) in DCM (2 mL) was added2-mercapitothiadiazole (44 mg, 0.36 mmol, 1.2 eq) and TEA (61 mg, 0.6mmol, 2.0 eq). The mixture was stirred at room temperature for 1 hbefore it was concentrated in vacuo. The residue was purified byprep-TLC (PE/EA=2:1) to give 20A (150 mg, 78%) as yellow solid.

Step 2: Synthesis of 20

To the solution of 20A (150 mg, 0.24 mmol, 1.0 eq) in dioxane (2 mL) wasadded i-BuB(OH)₂ (50 mg, 0.48 mmol, 2.0 eq) and concentrated HCl (2 mL).The reaction mixture was stirred at rt for 1 hour. The reaction mixturewas concentrated in vacuo, and the residue was dissolved in H₂O/MeCN.The resulting solution was adjusted to pH=12 and purified by prep-HPLC(C18, neutral) to give 20 (60 mg, 58%) as white solid.

ESI-MS: [M+H]⁺: 323

¹H NMR (400 MHz, CD₃OD/D₂O): δ 9.30 (s, 1H), 6.75 (d, J=4.4 Hz, 1H),6.59 (d, J=7.6 Hz, 1H), 4.51 (s, 2H), 2.57 (s, 2H), 0.43 (s, 2H).

Example 21Disodium;8-(3-aminopropylsulfanylmethyl)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 21A

To a solution of 19D (120 mg, 0.2 mmol, 1.0 eq) in DCM (3 mL) was added3-aminopropane-1-thiol (31 mg, 0.24 mmol, 1.2 eq) and TEA (42 mg, 0.4mmol, 2.0 eq). The reaction mixture was stirred at room temperature for2 hours before it was concentrated in vacuo. The residue was purified byprep-TLC (PE/EA=4:1) to give 21A (100 mg, 76%) as light yellow oil.

Step 2: Synthesis of 21

To a solution of 21A (100 mg, 0.16 mmol, 1.0 eq) in dioxane (2 mL) wasadded i-BuB(OH)₂ (33 mg, 0.32 mmol, 2.0 eq) and concentrated HCl (2 mL).The mixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated in vacuo, and the residue was dissolved inH₂O/MeCN. The resulting solution was adjusted to pH=12 and purified byprep-HPLC (C18, neutral) to give 21 (26 mg, 32%) as white solid.

ESI-MS: [M+H]⁺: 296

¹H NMR (400 MHz, CD₃OD/D₂O): δ 6.89 (m, 1H), 6.75-6.68 (m, 1H), 3.96 (s,2H), 2.86-2.80 (m, 2H), 2.67-2.62 (m, 2H), 2.59-2.55 (m, 2H), 1.88 (s,2H), 1.33-1.26 (m, 2H).

Example 22Disodium;8-[(5-amino-1,3,4-thiadiazol-2-yl)sulfanylmethyl]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 22A

To a solution of 19D (160 mg, 0.37 mmol, 1.0 eq) in DCM (20 mL) wasadded 2-amino-5-mercaptothiadiazole (45 mg, 0.52 mmol, 2.0 eq), TEA (61mg, 0.52 mmol, 2.0 eq) and DMF (5 mL). The mixture was stirred at roomtemperature for 1 hour. The mixture was then partitioned in H₂O and DCM.The organic layer was washed with water and brine, dried over Na₂SO₄.After concentration under reduced pressure, crude 22A (240 mg) wasobtained as yellow oil.

Step 2: Synthesis of 22

To a solution of 22A (240 mg, 0.37 mmol, 1.0 eq) in dioxane (5 mL) wasadded i-BuB(OH)₂ (77 mg, 0.74 mmol, 2.0 eq) and conc.HCl (5 mL). Themixture was stirred at room temperature for 2 hours. The reactionmixture was concentrated in vacuo, and the residue was dissolved inH₂O/MeCN. The resulting solution was adjusted to pH=12 and purified byprep-HPLC (C18, neutral) to give 22 (70 mg, 30%) as white solid.

ESI-MS: [M+H]⁺: 338

¹H NMR (400 MHz, CD₃OD/D₂O): δ 7.00 (d, J=7.6 Hz, 1H), 6.57 (d, J=8.0Hz, 1H), 4.79 (s, 2H), 2.67-2.62 (m, 2H), 1.29-1.25 (m, 2H).

Example 23Disodium;8-[[1-(2-aminoethyl)triazol-4-yl]methoxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 23A

The mixture of 19D (1.2 g, 2.33 mmol, 1.0 eq) and K₂CO₃ (0.963 g, 6.98mmol, 3.0 eq) in acetone (10 mL) was stirred at room temperature for 10minutes, followed by the addition of propargylbromide (0.83 g, 6.98mmol, 3.0 eq). The resulting mixture was stirred at 60° C. for 40 hours.The reaction was monitored by LC-MS. After filtration through a shortcelite pad, the filtrate was concentrated under reduced pressure and theresidue was purified by flash chromatography on silica (PE/EA=50:1 to5:1) to give 23A (0.78 g, 60%).

Step 2: Synthesis of 23B

To a solution of 23A (100 mg, 0.181 mmol, 1.0 eq) in dioxane (2 mL) wasadded 2-azido-N-Bocethylamine (40 mg, 0.215 mmol, 1.2 eq) and CuI (70mg, 0.362 mmol, 2.0 eq). The mixture was stirred at 60° C. for 3 hoursunder nitrogen atmosphere in a sealed tube. The reaction was monitoredby LC-MS. After filtration and concentration, the crude residue waspurified by prep-TLC (PE/EA=1:1) to give 23B (125 mg, 93%).

Step 3: Synthesis of 23

To a solution of 23B (100 mg, 0.18 mmol, 1.0 eq) in dioxane (3 mL) wasadded i-BuB(OH)₂ (37 mg, 0.36 mmol, 2.0 eq) and concentrated HCl (3 mL).The reaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was concentrated in vacuo, and the residue wasdissolved in H₂O/MeOH. The resulting solution was adjusted to pH=12 andpurified by prep-HPLC (C18, neutral) to give 23 (14.2 mg, 32%).

ESI-MS: [M+H]⁺: 333

¹H NMR (400 MHz, D₂O): δ 8.06 (s, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.65 (d,J=6.8 Hz, 1H), 5.29-5.22 (m, 2H), 4.74-4.62 (m, 2H), 3.80-3.25 (m, 2H),2.69-2.64 (m, 2H), 0.93-0.73 (m, 2H).

Example 24Disodium;4,4-dihydroxy-8-(1H-triazol-4-ylmethoxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 24A

To a solution of 23A (154 mg, 0.278 mmol, 1.0 eq) in dioxane (1.5 mL)were added TMSN₃ (560 mg, 4.86 mmol, 25.0 eq) and CuI (360 mg, 1.89mmol, 10.0 eq). The reaction mixture was stirred at 80° C. for 48 h. Thereaction was monitored by LC-MS. After filtration and concentration invacuo to remove the excessive TMSN₃, the crude product 24A (175 mg, 94%)was obtained, which was used directly for the next step.

Step 2: Synthesis of 24

To a solution of 24A (170 mg, 0.285 mmol, 1.0 eq) in dioxane (1.0 mL)was added i-BuB(OH)₂ (73 mg, 0.713 mmol, 2.5 eq) and concentrated HCl(1.0 mL). The reaction mixture was stirred at room temperature for 16hours. The reaction was monitored by LC-MS. The reaction mixture wasconcentrated in vacuo, and the residue was dissolved in H₂O/MeOH. Theresulting solution was adjusted to pH=9 and purified by prep-HPLC (C18,neutral) to give 24 (13.8 mg, 22%).

ESI-MS: [M+H]⁺: 290

¹H NMR (400 MHz, D₂O): δ 7.89 (s, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.38 (d,J=8.4 Hz, 1H), 5.21 (s, 2H), 2.58-2.55 (m, 2H), 0.41 (t, J=6.8 Hz, 2H).

Example 252-Hydroxy-7-prop-2-ynoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

Step 1: Synthesis 25

To a solution of 23A (100 mg, 0.18 mmol, 1.0 eq) in dioxane (3 mL) wasadded i-BuB(OH)₂ (37 mg, 0.36 mmol, 2.0 eq) and concentrated HCl (3 mL).The reaction mixture was stirred at rt for 16 hours. The reaction wasmonitored by LC-MS. The reaction mixture was concentrated in vacuo, andthe residue was purified by prep-HPLC (C18, 0.1% HCOOH as buffer) togive 25 (14.2 mg, 32%).

ESI-MS: [M+H]⁺: 247

¹H NMR (400 MHz, CD₃OD): δ 7.19 (d, J=8.0 Hz, 1H), 6.70 (d, J=8.0 Hz,1H), 4.80 (s, 2H), 2.99 (s, 1H), 2.69 (t, J=7.2 Hz, 2H), 1.06 (t, J=8.0Hz, 2H).

Example 267-(1,3-Dioxolan-2-ylmethoxy)-2-hydroxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

Step 1: Synthesis of 26A

A mixture of compound 15G (800 mg, 1.55 mmol, 1.0 eq),2-(bromomethyl)-1,3-dioxolane (780 mg, 4.65 mmol, 3.0 eq) and Cs₂CO₃(2.5 g, 7.75 mmol, 5.0 eq) in anhydrous DMF (40 mL) was stirred at roomtemperature overnight. The mixture was filtered and concentrated invacuo. The residue was purified by column chromatography (PE/EA=10:1) togive compound 26A (140 mg, 16.4%).

Step 2: Synthesis of 26

To a solution of compound 26A (140 mg) in dioxane (4 mL) andhydrochloric acid (1 mL) was added i-BuB(OH)₂ (50 mg, 0.46 mmol, 2 eq).The mixture was stirred at room temperature for 1 hour and was directlypurified by prep-HPLC to give 26 (14 mg, 9%) as white solid.

ESI-MS: [M+H]⁺: 295

H NMR (D₂O, 400 MHz): δ7.235-7.241 (m, 1H), 6.594-6.615 (d, J=8.4, 1H),5.252 (m, 1H), 4.764-4.863 (m, 2H), 4.148-4.165 (m, 2H), 3.936-3.941 (m,2H), 2.668-2.701 (m, 2H), 1.040-1.078 (m, 2H).

Example 27Disodium;4,4-dihydroxy-8-(2-morpholinoethoxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 27A

A solution compound 15G (600 mg, 1.163 mmol, 1.0 eq),4-(2-chloroethyl)morpholine hydrochloride (649 mg, 3.489 mmol, 3.0 eq)and Cs₂CO₃ (1.9 g, 5.8 mmol, 5.0 eq) in anhydrous DMF (12 mL) wasstirred at room temperature overnight. The solvent was removed underreduced pressure and the residue was purified by column chromatography(PE/EA=10:1) to give compound 27A (120 mg, 16.4%) as yellow oil.

Step 2: Synthesis of 27

To a solution of compound 27A (120 mg) in dioxane (2 mL) andhydrochloric acid (2 mL) was added i-BuB(OH)₂ (38.4 mg, 0.38 mmol, 2eq). The mixture was stirred at room temperature for 1 hour before itwas concentrated under reduced pressure. The residue was dissolved inH₂O/MeOH. The resulting solution was adjusted to pH=12 and purified byprep-HPLC (C18, neutral) to give 27 (54 mg, 9%) as white solid.

ESI-MS: [M+H]⁺: 322

¹H NMR (D₂O, 400 MHz): δ6.907-6.929 (d, J=8.8, 1H), 6.336-6.357 (d,J=8.4, 1H), 4.151-4.175 (m, 2H), 3.790-3.813 (m, 4H), 2.924-2.949 (m,2H), 2.790-2.798 (m, 4H), 2.573-2.607 (m, 2H), 0.391-0.425 (m, 2H).

Example 28Disodium;4,4-dihydroxy-8-(4-pyridylmethoxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 28A

The mixture of 15G (350 mg, 0.678 mmol, 1.0 eq) and K₂CO₃ (562 mg, 4.07mmol, 6.0 eq) in DMF (5 mL) was stirred at room temperature for 10minutes, followed by the addition of 4-(bromomethyl)pyridinehydrobromide (515 mg, 2.04 mmol, 3.0 eq). The resulting mixture wasstirred at room temperature for 16 hours. The reaction was monitored byLC-MS. After filtration through a short celite pad, the filtrate wasconcentrated under reduced pressure and the residue was purified byflash chromatography on silica (PE/EA=10:1-0:1) to give compound 28A(100 mg, 24%).

Step 2: Synthesis of 28

To a solution of 28A (60 mg, 0.099 mmol, 1.0 eq) in dioxane (2 mL) wasadded i-BuB(OH)₂ (25 mg, 0.247 mmol, 2.5 eq) and concentrated HCl (2mL). The mixture was stirred at rt for 3 hours. The reaction mixture wasconcentrated in vacuo, and the residue was dissolved in H₂O/MeOH. Theresulting solution was adjusted to pH=8 and purified by prep-HPLC (C18,neutral) to give 28 (5 mg, 20%) as white solid.

ESI-MS: [M+H]⁺: 300

¹H NMR (400 MHz, D₂O): δ 8.47 (s, 2H), 7.49 (s, 2H), 6.84 (s, 1H), 6.28(d, J=8.0 Hz, 1H), 5.17 (s, 2H), 2.57 (s, 2H), 0.41 (s, 2H).

Example 29Disodium;8-(2,2-difluoroethoxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis 29A

A mixture of compound 15G (500 mg, 0.968 mmol, 1.0 eq),1,1-difluoro-2-iodoethane (278.8 mg, 1.452 mmol, 1.5 eq) and Cs₂CO₃ (946mg, 2.90 mmol, 3.0 eq) in DMF (5 mL) was stirred at room temperature for2 hours. The reaction was monitored by LC-MS. After filtration through ashort celite pad, the filtrate was concentrated under reduced pressureand the residue was purified by prep-TLC (PE/EA=10:1) to give compound29A (160 mg, 28%).

Step 2: Synthesis 29

To a solution of 29A (150 mg, 0.259 mmol, 1.0 eq) in dioxane (1 mL) wasadded i-BuB(OH)₂ (52.4 mg, 0.518 mmol, 2.0 eq) and concentrated HCl (1mL). The reaction mixture was stirred at room temperature for 24 hours.The reaction mixture was concentrated in vacuo, and the residue wasdissolved in H₂O/MeCN. The resulting solution was adjusted to pH=12 andpurified by prep-HPLC (C18, neutral) to give 29 (55 mg, 72%).

ESI-MS: [M+H]⁺: 273

¹H NMR (400 MHz, CD₃OD/DMSO): δ 6.89 (d, J=8.0 Hz, 1H), 6.38-6.30 (m,1H), 6.17-6.15 (m, 1H), 4.24-4.17 (m, 2H), 3.32-3.29 (m, 2H), 0.53-0.49(m, 2H).

Example 30Disodium;4,4-dihydroxy-8-(4-hydroxybut-2-ynoxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 30B

A mixture of Compound 15G (500 mg, 0.969 mmol, 1.0 eq), compound 30A (J.Med. Chem., 1994, 37, 3739-48) (238 mg, 1.45 mmol, 1.5 eq) and Cs₂CO₃(948 mg, 2.91 mmol, 3.0 eq) in DMF (8 mL) was stirred at 50° C. for 12hours. The reaction was monitored by LC-MS. After filtration through ashort celite pad, the filtrate was concentrated under reduced pressureand the residue was purified by prep-TLC (PE/EA=5:1) to give compound30B (58 mg, 10%).

Step 2: Synthesis of 30

To a solution of compound 30B (58 mg, 0.099 mmol, 1.0 eq) in dioxane (1mL) was added i-BuB(OH)₂ (20 mg, 0.198 mmol, 2.0 eq) and concentratedHCl (1 mL). The reaction mixture was stirred at rt for 30 minutes. Thereaction mixture was concentrated in vacuo, and the residue wasdissolved in H₂O/MeCN. The resulting solution was adjusted to pH=12 andpurified by prep-HPLC (C18, neutral) to give compound 30 (24 mg, 81%).

ESI-MS: [M+H]⁺: 277

¹H NMR (400 MHz, CD₃OD): δ 6.72 (d, J=8.0 Hz, 1H), 6.29 (d, J=8.4 Hz,1H), 4.64-4.60 (m, 2H), 4.22-4.16 (m, 2H), 3.71-3.67 (m, 1H), 3.62-3.56(m, 1H), 2.53 (s, 1H), 0.42 (s, 2H).

Example 31Disodium;4,4-dihydroxy-8-(4-methoxybut-2-ynoxy)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 31B

To a solution of compound 31A (10 g, 0.116 mol, 1.0 eq) in DMSO (200 mL)was added KOH (6.6 g, 0.116 mol, 1.0 eq). The mixture was stirred atroom temperature for 30 min before MeI (16.5 g, 0.116 mol, 1.0 eq) wasadded dropwise. After 30 minutes at room temperature, the reactionmixture was poured into water and extracted with DCM (2×). The organiclayer was concentrated in vacuo and the residue was purified by flashchromatography on silica (PE/EA=5:1) to give compound 31B (2.3 g, 20%).

Step 2: Synthesis of 31C

To a solution of compound 31B (1.0 g, 10 mmol, 1.0 eq) in THF (10 mL)was added TEA (1.0 g, 10 mmol, 1.0 eq) at 0° C., followed by dropwiseaddition of MsCl (1.15 g, 10 mmol, 1.0 eq). The mixture was stirred atroom temperature for 30 minutes before it was concentrated to dryness.The residue was dissolved in EA and washed with water and brine. Theorganic phase was dried over Na₂SO₄ before it was concentrated in vacuoto give crude compound 31C (1.8 g, 100%).

Step 3: Synthesis of 31D

The mixture of compound 15G (1.0 g, 1.94 mmol, 1.0 eq), compound 31C(690 mg, 3.87 mmol, 2.0 eq) and Cs₂CO₃ (1.9 g, 5.81 mmol, 3.0 eq) in DMF(15 mL) was stirred at 50° C. for 12 hours under nitrogen atmosphere.The reaction was monitored by LC-MS. The mixture was filtered,concentrated under reduced pressure, and the residue was purified byflash chromatography on silica (PE/EA=5:1) to give compound 31D (600 mg,52%).

Step 4: Synthesis of 31

To a solution of compound 31D (300 mg, 0.50 mmol, 1.0 eq) in dioxane (2mL) was added i-BuB(OH)₂ (101 mg, 1.00 mmol, 2.0 eq) and concentratedHCl (2 mL). The reaction mixture was stirred at rt for 1 hour. Thereaction mixture was concentrated in vacuo, and the residue wasdissolved in H₂O/MeCN. The resulting solution was adjusted to pH=12 andpurified by prep-HPLC (C18, neutral) to give compound 31 (52 mg, 33%).

ESI-MS: [M+H]⁺: 291

¹H NMR (400 MHz, CD₃OD): δ 6.82 (d, J=8.4 Hz, 1H), 6.38 (d, J=8.0 Hz,1H), 4.76 (s, 2H), 4.14-4.09 (m, 2H), 3.37-3.35 (m, 3H), 2.62-2.56 (m,2H), 0.54-0.50 (m, 2H).

Example 32Disodium;8-(4-aminobut-2-noxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 32B

The mixture of compound 15G (600 mg, 1.16 mmol, 1.0 eq), 32A (Bioorg.Med. Chem. Lett., 2010, 20, 3165-68) (450 mg, 1.71 mmol, 1.5 eq) andCs₂CO₃ (1.1 g, 3.38 mmol, 3.0 eq) in DMF (10 mL) was stirred at 50° C.for 12 hours under nitrogen atmosphere. The reaction was monitored byLC-MS. The mixture was filtered and concentrated under reduced pressure.The residue was purified by flash chromatography on silica (PE/EA=4:1)to give compound 32B (340 mg, 43%).

Step 6: Synthesis of 32

To a solution of compound 32B (300 mg, 0.44 mmol, 1.0 eq) in dioxane (3mL) was added i-BuB(OH)₂ (89 mg, 0.88 mmol, 2.0 eq) and concentrated HCl(2 mL). The reaction mixture was stirred at rt for 1 hour. The reactionmixture was concentrated in vacuo, and the residue was dissolved inH₂O/MeCN. The resulting solution was adjusted to pH=12 and purified byprep-HPLC (C18, neutral) to give compound 32 (31 mg, 24%).

ESI-MS: [M+H]⁺: 276

¹H NMR (400 MHz, CD₃OD): δ 6.96 (d, J=7.6 Hz, 1H), 6.45 (d, J=8.8 Hz,1H), 5.57 (s, 4H), 3.65-3.41 (m, 2H), 2.62-2.57 (m, 2H), 0.81-0.76 (m,2H).

Example 33(2-Hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaborinin-8-yl)phosphonic acid

Step 1: Synthesis of 33B

To the solution of 33A (9.8 g, 79 mmol, 1.0 eq) in DCM (100 mL) wasadded NBS (14.8 g, 82.9 mmol, 1.05 eq) in DCM (150 mL) dropwise at 0° C.The reaction mixture was stirred at room temperature for 2 hours undernitrogen atmosphere before it was concentrated in vacuo to dryness. Theresidue was purified by flash chromatography on silica (PE/EA=20:1 to5:1) to give 33B (10.2 g, 64%).

Step 2: Synthesis of 33C

To a solution of 33B (9.2 g, 45.5 mmol, 1.0 eq) in DCM (100 mL) wasadded diethyl phosphorochloridate (8.64 g, 50.1 mmol, 1.1 eq) and Et₃N(6.9 g, 68.3 mmol, 1.5 eq) dropwise. The mixture was stirred at roomtemperature for 16 hours before it was concentrated to dryness. Theresidue was purified by column chromatography (PE/EA=10:1 to 5:1) togive 33C (13.9 g, 90%).

Step 3: Synthesis of 33D

To a solution of 33C (13.9 g, 0.04 mol, 1.0 eq) in anhydrous THF (150mL) was added LDA (36 mL, 2M in THF, 0.072 mol, 1.8 eq) dropwise at −78°C. The reaction mixture was slowly warmed to room temperature in 2 hoursbefore it was quenched with saturated aqueous NH₄Cl. The mixture wasextracted with EA and dried over Na₂SO₄. The crude product was purifiedby column chromatography (PE/EA=20:1 to 5:1) to give 33D (8.8 g, 63%).

Step 4: Synthesis of 33E

A mixture of 33D (3.0 g, 8.88 mmol, 1.0 eq), CH₂CHBF₃K (2.38 g, 17.75mmol, 2.0 eq), PdCl₂ (dppf) (579 mg, 0.71 mmol, 0.08 eq) and DIPEA (3.4g, 26.6 mmol, 3.0 eq) in dioxane (30 mL) was stirred at 100° C. for 16hours under nitrogen atmosphere. The reaction was monitored by TLC. Themixture was filtered, evaporated to dryness, and purified by columnchromatography (PE/EA=20:1 to 10:1) to give compound 33E (1.4 g, 55%).

Step 5: Synthesis of 33F

To the solution of 33E (1.4 g, 4.89 mmol, 1.0 eq) in DCM (15 mL) wasadded Boc₂O (1.6 g, 7.34 mmol, 1.5 eq), TEA (1.49 g, 14.7 mmol, 3.0 eq)and DMAP (60 mg, 0.49 mmol, 0.1 eq). The mixture was stirred at roomtemperature for 16 hours before it was evaporated to dryness. Theresidue was purified by column chromatography (PE/EA=5:1 to 2:1) to give33F (1.9 g, 100%).

Step 6: Synthesis of 33G

To a mixture of 33F (300 mg, 0.78 mmol, 1.0 eq) in DCM (3 mL) was added4,4,5,5-tetramethyl-1,3,2-dioxaborolane (199 mg, 1.55 mmol, 2.0 eq),[IrCl(COD)]₂ (10.4 mg, 0.016 mmol, 0.02 eq) and dppe (12.4 mg, 0.03mmol, 0.04 eq). The mixture was stirred at room temperature for 16 hoursbefore it was evaporated to dryness. The residue was purified by columnchromatography (PE/EA=5:1 to 1:1) to give 33G (350 mg, 88%).

ESI-MS: [M+H]⁺: 515

Step 7: Synthesis of 33

To a solution of 33G (200 mg, 0.39 mmol, 1.0 eq) in DCM (5 mL) was addedTMSBr (298 mg, 1.95 mmol, 8.0 eq). The mixture was stirred at roomtemperature for 16 hours before it was concentrated. The residue waspurified by pre-HPLC (C18) to give 33 (39.5 mg, 39%) as white solid.

ESI-MS: [M+H]⁺: 259

¹H NMR (400 MHz, CD₃OD): δ 7.19 (d, J=8.4 Hz, 1H), 6.43-6.38 (m, 1H),3.82 (d, J=12.4 Hz, 3H), 2.61-2.56 (m, 2H), 1.06-1.01 (m, 2H).

Example 346-Fluoro-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

Step 1: Synthesis of 34B

To a solution of 34A (500 mg, 3.52 mmol, 1.0 eq) in THF (5 mL) was addedBoc₂O (921 mg, 4.23 mmol, 1.2 eq) and DMAP (22 mg, 0.17 mmol, 0.05 eq).The mixture was stirred at room temperature for 2 hours before it wasconcentrated in vacuo. The residue was purified by column chromatography(PE/EA=20:1 to 5:1) to give 34B (767 mg, 90%).

Step 2: Synthesis of 34C

To a solution of 34B (5.0 g, 20.7 mmol, 1.0 eq) in anhydrous THF (50 mL)was added LDA (26 mL, 2M in THF, 52 mmol, 2.5 eq, freshly made) dropwise−78 OC. The reaction mixture was slowly warmed to room temperature in 2hours before it was quenched with saturated aqueous NH₄Cl. The mixturewas extracted with EA and dried over Na₂SO₄. The crude product waspurified by column chromatography (PE/EA=20:1 to 5:1) to give 34C (3.6g, 75%).

Step 3: Synthesis of 34D

To a solution of 34C (3.6 g, 14.9 mmol, 1.0 eq) in DCM (40 mL) was addedNBS (2.9 g, 16.4 mmol, 1.1 eq) and DIA (300 mg, 2.98 mmol, 0.2 eq). Thereaction mixture was stirred at room temperature for 0.5 hour. Thereaction was monitored by TLC. The mixture was evaporated to dryness,and the residue was purified by column chromatography (PE/EA=20:1 to5:1) to give 34D (1.9 g, 40%).

Step 4: Synthesis of 34E

To a solution of 34D (1.9 g, 5.9 mmol, 1.0 eq) in THF (20 mL) was addedBoc₂O (1.5 g, 7.08 mmol, 1.2 eq) and DMAP (36 mg, 0.295 mmol, 0.05 eq).The mixture was stirred at room temperature for 2 hours before it wasconcentrated in vacuo. The residue was purified by column chromatography(PE/EA=20:1 to 5:1) to give 34E (2.5 g, 100%).

Step 5: Synthesis of 34G

To a solution of 34E (2.47 g, 5.9 mmol, 1.0 eq) and Pd(t-Bu₃P)₂ (300 mg,0.59 mmol, 0.1 eq) in THF (30 mL) was added 34F (WO 0946098) (freshlymade, about 8.8 mmol in THF, 1.5 eq) dropwise over 10 min under N₂. Themixture was stirred at room temperature overnight before it wasconcentrated in vacuo. The residue was purified by column chromatography(PE/EA=10:1) to give 34G (660 mg, 23%).

ESI-MS: [M+H]⁺: 535

Step 6: Synthesis of 34H

To a solution of 34G (300 mg, 0.56 mmol, 1.0 eq) and CH₂ICl (198 mg,1.12 mmol, 2.0 eq) in THF (3 mL) was added n-BuLi (0.4 mL, 2.5 M inhexanes, 0.96 mmol, 1.7 eq) dropwise in 10 minutes at −78° C. Themixture was slowly warmed up to room temperature overnight. The mixturewas concentrated in vacuo and the residue was purified by prep-TLC(PE/EA=5:1) to give 34H (220 mg, 71%).

ESI-MS: [M+H]⁺: 549

Step 7: Synthesis of 34

To a solution of 34H (220 mg, 0.40 mmol, 1.0 eq) in dioxane (3 mL) wasadded i-BuB(OH)₂ (82 mg, 0.80 mmol, 2.0 eq) and concentrated HCl (2 mL).The reaction mixture was stirred at room temperature for 3 hours. Thereaction mixture was concentrated in vacuo, and the residue wasdissolved in H₂O/MeCN. The resulting solution was adjusted to pH=10-12with 1N NaOH and purified by prep-HPLC (C18, neutral) to give 34 (18 mg,19%).

ESI-MS: [M+H]⁺: 241

¹H NMR (400 MHz, CD₃OD): δ 7.06 (s, 1H), 3.80 (s, 3H), 2.72-2.68 (m,2H), 1.10-1.05 (m, 2H).

Example 356,7-Difluoro-2-hydroxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylic acid

Step 1: Synthesis of 35B

To a solution of 35A (400 mg, 3.1 mmol, 1.0 eq) in THF (5 mL) was addedBoc₂O (811 mg, 3.7 mmol, 1.2 eq) and DMAP (20 mg, 0.16 mmol, 0.05 eq).The mixture was stirred at rt for 2 hours before it was concentrated invacuo. The residue was purified by column chromatography (PE/EA=10:1) togive 35B (470 mg, 66%).

Step 2: Synthesis of 35C

To a solution of 35B (470 mg, 2.04 mmol, 1.0 eq) in anhydrous THF (20mL) was added LDA (1.5 mL, 2M in THF, 3.06 mmol, 1.5 eq) dropwise at−78° C. The mixture was slowly warmed up to room temperature in 6 hoursbefore it was quenched with saturated aqueous NH₄Cl solution. Themixture was extracted with EA and dried over Na₂SO₄. The organic layerwas concentrated, and the residue was purified by column chromatography(PE/EA=20:1) to give 35C (317 mg, 67%).

Step 3: Synthesis of 35D

To a solution of 35C (317 mg, 1.38 mmol, 1.0 eq) in DCM (100 mL) wasadded DIA (27.9 mg, 0.276 mmol, 0.2 eq) and NBS (259 mg, 82.9 mmol, 1.05eq). The mixture was stirred at room temperature for 16 hours before itwas filtered and concentrated under vacuum to give crude 35D (436 mg,100%).

Step 4: Synthesis of 35E

To a solution of 35D (436 mg, 1.41 mmol, 1.0 eq) in DCM (2 mL) was addedBoc₂O (323 mg, 1.48 mmol, 1.05 eq) and DMAP (9 mg, 0.07 mmol, 0.05 eq).The mixture was stirred at room temperature for 1 hours before it wasevaporated to dryness. The residue was purified by column chromatography(PE/EA=200:1 to 100:1) to give 35E (475 mg, 82%).

Step 5: Synthesis of 35F

A mixture of 35E (475 mg, 1.16 mmol, 1.0 eq), CH₂CHBF₃K (310 mg, 2.32mmol, 2.0 eq), PdCl₂ (dppf) (76 mg, 0.09 mmol, 0.08 eq) and DIPEA (448mg, 3.47 mmol, 3.0 eq) in dioxane (5 mL) was stirred at 80° C. for 16hours under nitrogen atmosphere. The reaction was monitored by TLC. Themixture was filtered and the filtrate was purified by columnchromatography (PE/EA=100:1 to 30:1) to give 35F (240 mg, 58%).

Step 6: Synthesis of 35G

To a solution of 35F (240 mg, 0.67 mmol, 1.0 eq) in DCM (2 mL) was added4,4,5,5-tetramethyl-1,3,2-dioxaborolane (172 mg, 1.34 mmol, 2.0 eq),[IrCl(COD)]₂ (9 mg, 0.013 mmol, 0.02 eq) and dppe (11 mg, 0.027 mmol,0.04 eq). The mixture was stirred at room temperature for 16 hours undernitrogen atmosphere. The reaction was monitored by TLC. The mixture wasconcentrated and purified by prep-TLC (PE/EA=20:1) to give 35G (107 mg,33%).

ESI-MS: [M+H]⁺: 485

Step 7: Synthesis of 35

To a solution of 35G (100 mg, 0.207 mmol, 1.0 eq) in DCM (2 mL) at 0° C.was added 90% TFA (0.5 mL). The mixture was stirred at room temperaturefor 5 hours before it was concentrated in vacuo. The residue waspurified by pre-HPLC (C18) to give 35 (12.9 mg, 27%) as white solid.

ESI-MS: [M+CH₃CN+H]⁺=270

¹H NMR (400 MHz, CD₃OD): δ 7.27-7.16 (m, 1H), 2.70-2.56 (m, 2H),1.07-0.95 (m, 2H).

Example 36Disodium;4,4-dihydroxy-8-methylsulfanyl-5-oxa-4-boranuidabicyclo[4.4.0]deca-(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 36B

A mixture of 36A (WO 15179308) (3.0 g, 7.7 mmol, 1.0 eq) and MeSNa (1.08g, 15.4 mmol, 2.0 eq) in DMF (20 mL) was stirred at room temperature for16 hours under nitrogen atmosphere. The reaction was monitored by TLC.The reaction mixture was concentrated in vacuo and purified by columnchromatography (EA/PE, 1:5) to obtain 36B (1.41 g, 44%).

Step 2: Synthesis of 36C

To a mixture of 36B (1 g, 2.39 mmol, 1.0 eq), CH₂CHBF₃K (801 mg, 5.98mmol, 2.5 eq) and Cs₂CO₃ (2.34 g, 7.18 mmol, 3.0 eq) in THF/H₂O (9 mL/1mL) was added PdCl₂ (dppf) (300 mg, 0.367 mmol, 0.15 eq). The reactionmixture was stirred at room temperature for 16 hours under nitrogenatmosphere. The reaction was monitored by TLC. The mixture was filteredand washed with EA. The filtrate was concentrated and purified by columnchromatography (PE/EA=20:1) to give 36C (600 mg, 68%).

Step 3: Synthesis of 36D

To a solution of 36C (700 mg, 1.91 mmol, 1.0 eq) in DCM (7 mL) was added4,4,5,5-tetramethyl-1,3,2-dioxaborolane (489 mg, 3.82 mmol, 2.0 eq),[IrCl(COD)]₂ (38.5 mg, 0.057 mmol, 0.03 eq) and dppe (46 mg, 0.114 mmol,0.06 eq). The mixture was stirred at room temperature for 20 hours undernitrogen atmosphere before it was concentrated in vacuo. The residue waspurified by column chromatography (PE/EA=20:1 to 5:1) to give 36D (130mg, 14%).

ESI-MS: [M+H]⁺:495

Step 4: Synthesis of 36E

A solution of 36D (120 mg, 0.243 mmol, 1.0 eq) in 90% THF (1 mL) and DCM(1 mL) was stirred at room temperature for 2 hours. The reaction mixturewas concentrated and the residue was dissolved in MeCN/water. Theresulting solution was adjusted to pH=10 with 1N NaOH and purified byprep-HPLC (C18, neutral) to give 36E (28 mg, 44%) as white solid.

ESI-MS: [M−H2O+H]⁺: 221

¹H NMR (400 MHz, CD₃OD/D₂O): δ 7.06 (d, J=8.4 Hz, 1H), 6.60 (d, J=8.0Hz, 1H), 2.65-2.61 (m, 2H), 2.32 (s, 3H), 0.71-0.67 (m, 2H).

Example 37Disodium;9-fluoro-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 37B

A mixture of 37A (5.1 g, 33 mmol, 1.0 eq) and NBS (6.4 g, 36 mmol, 1.1eq) in AcOH (25 mL) was stirred at 80° C. for 24 hours. The reaction wasmonitored by TLC. The mixture was concentrated in vacuo and the residuewas purified by column chromatography (PE/EA=2:1 to 1:1) to give 37B(6.5 g, 85%).

ESI-MS: [M−H]⁻: 233, 235

Step 2: Synthesis of 37C

A mixture of 37B (6.1 g, 26 mmol, 1.0 eq), Boc₂O (28 g, 130 mmol, 5.0eq) and DMAP (3.2 g, 26 mmol, 1.0 eq) in t-BuOH/THF (60 mL/40 mL) wasstirred at 60° C. for 16 hours. The mixture was concentrated in vacuoand the residue was purified by column chromatography (PE/EA=10:1 to5:1) to give 37C (1.5 g, 15%).

Step 3: Synthesis of 37D

A mixture of 37C (1.6 g, 4.75 mmol, 1.0 eq), CH₂CHBF₃K (1.27 g, 9.5mmol, 2.0 eq), DIPEA (1.84 g, 14.2 mmol, 3.0 eq) and PdCl₂ (dppf) (310mg, 0.38 mmol, 0.08 eq) in dioxane (20 mL) was stirred at 85° C. for 16hours under nitrogen atmosphere. The mixture was filtered and washedwith EA. The filtrate was concentrated and purified by columnchromatography (PE/EA=20:1) to give 37D (900 mg, 65%).

Step 4: Synthesis of 37E

To a solution of 37D (347 mg, 1.03 mmol, 1.0 eq) in DCM (4 mL) was added4,4,5,5-tetramethyl-1,3,2-dioxaborolane (263 mg, 2.05 mmol, 2.0 eq),[IrCl(COD)]₂ (21 mg, 0.031 mmol, 0.03 eq) and dppe (25 mg, 0.062 mmol,0.06 eq). The mixture was stirred at room temperature for 5 hours beforeit was concentrated. The residue was purified by column chromatography(PE/EA=10:1 to 5:1) to give 37E (120 mg, 25%).

ESI-MS: [M+H]⁺: 467

Step 5: Synthesis of 37

A solution of 37E (100 mg, 0.215 mmol, 1.0 eq) in 90% THF (2.5 mL) andDCM (2.5 mL) was stirred at room temperature for 2 hours. The mixturewas concentrated and purified by prep-HPLC (C18). The obtained solid wasdissolved in MeCN/H₂O and was adjusted to pH=9 with 0.1 N NaOH. Afterlyophilization, the Na salt of 37 (70 mg, 100%) was obtained as whitesolid.

ESI-MS: [M+MeCN+H]⁺: 252

¹H NMR (400 MHz, CD₃OD): δ 6.98 (d, J=6.4 Hz, 1H), 6.61 (d, J=6.4 Hz,1H), 2.65-2.60 (m, 2H), 0.48-0.44 (m, 2H).

Example 38Disodium;8,8-dihydroxy-7-oxa-2-aza-8-boranuidabicyclo[4.4.0]deca-1,3,5-triene-5-carboxylate

Step 1: Synthesis of 38B

A solution of compound 38A (5.0 g, 38.6 mmol, 1.0 eq), (Boc₂)O (9.17 g,42.4 mmol, 1.1 eq) and DMAP (0.472 g, 3.86 mmol, 0.1 eq) in anhydrousDCM (100 mL) was stirred at room temperature for 0.5 hour. The solventwas removed under reduced pressure and the residue was purified bycolumn chromatography (PE/EA=5:1) to give compound 38B (8.0 g, 90%).

ESI-MS: [M+H]⁺: 230

Step 2: Synthesis of 38C

To a solution of compound 38B (4.0 g, 17.4 mmol, 1.0 eq) in anhydrousTHF (50 ml) was slowly added LDA (10.5 mL, 2 M in THF, 20.9 mmol, 1.2eq) over 10 minutes at −78° C. The mixture was warmed up and stirred atroom temperature for 2 hours before it was quenched by saturated NH₄Clsolution. The organic layer was concentrated under reduced pressure andthe residue was purified by column chromatography (PE/EA=51) to givecompound 38C (0.9 g, 23%).

ESI-MS: [M+H]⁺: 230

Step 3: Synthesis of 38D

A solution of compound 38C (0.8 g, 3.5 mmol, 1.0 eq), potassiumvinyltrifluoroborate (0.61 g, 4.53 mmol, 1.3 eq), TEA (1.06 g, 10.5mmol, 3.0 eq) and PdCl₂ (dppf) (0.256 g, 0.35 mmol, 0.1 eq) in dioxane(10 ml) was stirred at 80° C. for 10 hours under N₂. After cooled down,the mixture was filtered and the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography (PE/EA=10:1)to give compound 38D (0.58 g, 67%).

ESI-MS: [M+H]⁺: 222

Step 4: Synthesis of 38E

A solution of compound 38D (0.53 g, 2.4 mmol, 1.0 eq), (Boc₂)O (0.68 g,3.1 mmol, 1.3 eq) and DMAP (0.147 g, 1.2 mmol, 0.5 eq) in anhydrous DCM(6 mL) was stirred at room temperature for 1 hour. The solution wasconcentrated under reduced pressure and the residue was purified bycolumn chromatography (PE/EA=10:1) to give compound 38E (0.76 g, 98%).

ESI-MS: [M+H]⁺: 322

Step 5: Synthesis of 38F

A solution of compound 38E (0.3 g, 0.94 mmol, 1.0 eq), Bin₂Pin₂ (0.275g, 1.08 mmol, 1.15 eq), Cu₂O (11 mg, 0.076 mmol, 0.08 eq), K₂HPO₄ (0.197g, 1.13 mmol, 1.2 eq) and PPh₃ (0.028 g, 0.104 mmol, 0.11 eq) in MeOH (3mL) was stirred at 85° C. for 4 hours under N₂. The mixture was filteredand the filtrate was concentrated in vacuo to give crude compound 38F(400 mg, 94%).

ESI-MS: [M+H]⁺: 450

Step 6: Synthesis of 38

A solution of crude compound 38F (0.4 g, 0.9 mmol, 1.0 eq) in 90% aq TFA(3 mL) and Et₃SiH (3 mL) was stirred overnight at 30° C. The solvent wasremoved in vacuo, and the residue was dissolved in H₂O/MeCN. Theresulting solution was adjusted to pH=12 with 1N NaOH and purified byprep-HPLC (C18, neutral) to give 38 (37 mg, 30%) as white solid.

ESI-MS: [M+H]⁺: 194

¹H NMR (CD₃OD, 400 MHz): δ 7.475-7.473 (d, 1H), 7.001 (d, 1H),2.535-2.435 (t, J=20, 2H), 0.289-0.253 (t, J=7.2, 2H)

Example 392-Hydroxy-7-methylsulfonyl-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

Step 1: Synthesis of 39A

To a solution of 36B (1.4 g, 3.35 mmol, 1.0 eq) in DCM (40 mL) was addedm-CPBA (1.73 g, 10 mmol, 3.0 eq) slowly at 0° C. The mixture was slowlywarmed up to room temperature in 3 hours. The reaction was monitored byTLC. The mixture was quenched with aqueous Na2S2O3 and washed withwater. The organic layer was dried over Na₂SO₄ and then concentrated invacuo to give crude 39A (1.31 g, 87%).

Step 2: Synthesis of 39B

A mixture of 39A (1.3 g, 2.88 mmol, 1.0 eq), CH₂CHBF₃K (0.77 g, 5.76mmol, 2.0 eq), PdCl₂ (dppf) (169 mg, 0.23 mmol, 0.08 eq) and DIPEA (1.83g, 14.2 mmol, 3.0 eq) in dioxane (20 mL) was stirred at 85° C. for 16hours under nitrogen atmosphere. The reaction was monitored by TLC. Themixture was filtered and concentrated in vacuo. The residue was purifiedby column chromatography to give 39B (870 mg, 76%).

ESI-MS: [M+H]⁺: 399

Step 3: Synthesis of 39C

To a solution of 39B (770 mg, 1.93 mmol, 1.0 eq) in DCM (7 mL) was added4,4,5,5-tetramethyl-1,3,2-dioxaborolane (495 mg, 3.87 mmol, 2.0 eq),[IrCl(COD)]₂ (26 mg, 0.039 mmol, 0.02 eq) and dppe (31 mg, 0.077 mmol,0.04 eq). The mixture was stirred at room temperature for 20 hours undernitrogen atmosphere. The reaction was monitored by TLC. The mixture wasconcentrated in vacuo, the residue was purified by prep-TLC to give 39C(120 mg, 12%).

ESI-MS: [M+H]⁺: 527

Step 4: Synthesis of 39

The solution of 39C (110 mg, 0.21 mmol, 1.0 eq) in 90% THF (1 mL) andDCM (4 mL) was stirred at room temperature for 2 hours. The reactionmixture was concentrated and the residue was dissolved in MeCN/water.The resulting solution was purified by prep-HPLC to give 39 (17 mg,30%).

ESI-MS: [M−H2O+H]⁺: 253

¹H NMR (400 MHz, CD₃OD): δ 7.55 (d, J=7.6 Hz, 1H), 7.42-7.39 (m, 1H),3.19 (s, 3H), 2.91-2.86 (m, 2H), 1.11-1.06 (m, 2H).

Example 40Disodium;4,4-dihydroxy-8-methylsulfinyl-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 40A

To the solution of compound 36B (2.0 g, 4.79 mmol, 1.0 eq) in anhydrousDCM (10 mL) was added m-CPBA (0.827 g, 4.79 mmol, 1.0 eq) in DCM (2 mL)at −78° C. The reaction mixture was stirred at −78° C. for 2 hoursbefore it was quenched with aqueous Na₂S₂O₃. The reaction mixture waspartitioned in DCM and H₂O. After dried over Na₂SO₄ the organic layerwas concentrated in vacuo. The residue was purified by columnchromatography (PE/EA=5:1) to give compound 40A (2.02 g, 97%).

Step 2: Synthesis of 40B

A solution of compound 40A (2.02 g, 4.66 mmol, 1.0 eq), potassiumvinyltrifluoroborate (1.56 g, 11.5 mmol, 2.5 eq), Cs₂CO₃ (4.46 g, 13.7mmol, 3.0 eq) and PdCl₂ (dppf) (1.03 g, 1.4 mmol, 0.3 eq) in THF/H₂O (30ml, 9/1, v/v) was stirred at 85° C. overnight under N₂. The mixture wasfiltered and solvent was removed under reduced pressure. The residue waspurified by column chromatography (PE/EA=5:1) to give compound 40B (1.56g, 88%).

ESI-MS: [M+H]⁺: 383

Step 3: Synthesis of 40C

To a solution of 40B (500 mg, 1.31 mmol, 1.0 eq) in anhydrous DCM (7 mL)was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (336 mg, 2.62 mmol,2.0 eq), [IrCl(COD)]₂ (27 mg, 0.04 mmol, 0.03 eq) and dppe (32 mg, 0.08mmol, 0.06 eq). The mixture was stirred at room temperature for 20 hoursunder nitrogen atmosphere. The reaction was monitored by TLC. Themixture was concentrated in vacuo, the residue was purified by columnchromatography (PE/EA=5:1) to give compound 40C (0.59 g, 89%).

ESI-MS: [M+H]⁺: 511

Step 4: Synthesis of 40

A solution of compound 40C (300 mg, 0.59 mmol, 1.0 eq) in 90% TFA (2 mL)and DCM (2 mL) was stirred at room temperature for 3 h. The reactionmixture was concentrated and the residue was dissolved in MeCN/water.The resulting solution was adjusted to pH=10 with 1N NaOH and purifiedby prep-HPLC (C18, neutral) to give 40 (50 mg, 33%) as white solid.

ESI-MS: [M+H]⁺: 255

¹H NMR (CD3OD, 400 MHz): δ 7.439-7.420 (m, 1H), 7.382-7.364 (m, 1H),2.840 (s, 3H), 2.743-2.704 (t, J=8 Hz, 2H), 1.036-10.17 (t, J=7.6 Hz,2H)

Example 416-Chloro-2-hydroxy-7-methoxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

Step 1: Synthesis of 41B

To a solution of compound 41A (10.0 g, 40 mmol, 1.0 eq) in AcOH (100 mL)was added SO₂Cl₂ (11.0 g, 0.08 mol, 2.0 eq) dropwise over 5 min at roomtemperature. The reaction mixture was stirred at 40° C. overnight beforeit was concentrated in vacuo. The residue was purified by columnchromatography (PE/EA=3:1) to give compound 41B (8.5 g, 80%).

Step 2: Synthesis of 41C

To a solution of compound 41B (8.5 g, 35.6 mmol, 1.0 eq) in t-BuOH/THF(200 mL, 1/1, v/v) was added (Boc)₂O (31 g, 142 mmol, 4.0 eq) and DMAP(427 mg, 3.5 mmol, 0.1 eq) over 20 minutes. The mixture was stirred at65° C. overnight before it was concentrated in vacuo. The residue waspurified by column chromatography (PE/EA=10:1) to give compound 41C (13g, 75%).

Step 3: Synthesis of 41E

To a solution of compound 41C (13 g, 30 mmol, 1.0 eq) and Pd(PBu₃)₂ (1.5g, 2.98 mmol, 0.1 eq) in anhydrous THF (400 mL) was added a solution of41D (WO 15179308) (freshly made, about 40 mmol in THF, 1.3 eq) dropwiseover 10 min under N₂. The mixture was stirred at room temperatureovernight before it was concentrated in vacuo. The residue was purifiedby column chromatography (PE/EA=10:1) to give compound 41E (8.8 g, 60%).

ESI-MS: [M+H]⁺: 551

Step 4: Synthesis of 41F

To a solution of compound 41E (500 mg, 0.91 mmol, 1.0 eq) and CH₂ICl(319 mg, 1.82 mmol, 2.0 eq) in anhydrous THF (15 mL) was slowly addedn-BuLi (0.54 mL, 2.5 M in hexanes, 1.36 mmol, 1.5 eq) over 10 minutes at−78° C. The mixture was slowly warmed up to room temperature overnight.The reaction solution was concentrated in vacuo and the residue waspurified by column chromatography (PE/EA=10:1) to give compound 41F(0.46 g, 80%).

ESI-MS: [M+H]⁺: 565

Step 5: Synthesis of 41

To a solution of compound 41F (0.46 g, 0.816 mmol, 1.0 eq) in dioxane (4mL) and concentrated HCl (4 mL) was added i-BuB(OH)₂ (166 mg, 1.63 mmol,2.0 eq). The mixture was stirred at room temperature for 1 hours. Thereaction mixture was concentrated under reduced pressure and the mixturewas purified by prep-HPLC (C18) to give 41 (21 mg, 15%) as white solid.

ESI-MS: [M+H]⁺: 257

¹H NMR (CD₃OD, 400 MHz): δ 7.260 (s, 1H), 3.858 (s, 3H), 2.723-2.684 (t,J=8.0, J=7.6, 2 H), 1.080-1.041 (t, J=7.6, J=8.0, 2 H)

Example 42Disodium;4,4,8-trihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

To the mixture of compound 15G (500 mg, 0.97 mmol, 1.0 eq), i-BuB(OH)₂(148 mg, 1.45 mmol, 1.5 eq) in hexane (9 mL) and methanol (9 mL) wasadded about 10 drops of concentrated HCl at 0° C. The reaction mixturewas stirred at room temperature overnight. The methanol layer wasseparated and washed with hexanes (2×). The methanol layer was thenconcentrated and the residue was added 90% aqueous TFA (6 mL) and TES (2mL). The mixture was stirred at room temperature for 1 hours before itwas concentrated under reduced pressure. The residue was dissolved inMeCN/water and adjusted to pH=12 with 0.1 N NaOH. The resulting solutionwas purified by prep-HPLC (C18, neutral) to give 42 (6 mg, 10%) asyellow solid.

ESI-MS: [2M−H]⁻: 415

¹H NMR (CD₃OD, 400 MHz): δ 6.950 (d, 1H), 6.169-6.148 (d, J=8.4, 1 H),2.573-2.535 (t, J=8.0, J=7.2, 2 H), 0.896-0.878 (t, 2H)

Example 43Disodium;8-(2-fluoroethoxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 43A

The mixture of compound 15G (500 mg, 0.97 mmol, 1.0 eq),1-fluoro-2-iodoethane (340 mg, 1.94 mmol, 2.0 eq) and Cs₂CO₃ (947 mg,2.9 mmol, 3.0 eq) in anhydrous DMF (15 mL) was stirred at roomtemperature overnight. The solvent was removed under reduced pressureand the residue was purified by column chromatography (PE/EA=10:1) togive compound 43A (300 mg, 70%).

ESI-MS: [M+H]⁺: 563

Step 2: Synthesis of 43

To a solution of compound 43A (200 mg, 0.36 mmol, 1.0 eq) in dioxane (3mL) and concentrated HCl (3 mL) was added i-BuB(OH)₂ (73 mg, 0.71 mmol,2.0 eq). The mixture was stirred at rt for 1 hour. The reaction mixturewas concentrated in vacuo, and the residue was dissolved in H₂O/MeCN.The resulting solution was adjusted to pH=12 with 1N NaOH and purifiedby prep-HPLC (C18, neutral) to give 43 (62 mg, 50%) as white solid.

ESI-MS: [M+H]⁺: 255

¹H NMR (CD₃OD, 400 MHz): δ 6.787-6.766 (d, J=8.4, 1 H), 6.255-6.235 (d,J=8.0, 1 H), 4.736-4.715 (t, J=4.0, J=4.4, 1 H), 4.616-4.596 (t, 1H),4.197-4.176 (t, 1H), 4.126-4.104 (t, 1H), 2.591-2.556 (t, 2H),0.507-0.473 (t, J=6.8, 2 H)

Example 442-hydroxy-7-[2-hydroxy-1-(hydroxymethyl)ethoxy]-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

Step 1: Synthesis of 44A

To a solution of compound 15G (800 mg, 1.55 mmol, 1.0 eq) and3-iodooxetane (485 mg, 2.63 mmol, 1.7 eq) in anhydrous DMF (15 mL) wasadded Cs₂CO₃. The mixture was stirred at 50° C. overnight before it wasconcentrated under reduced pressure. The residue was purified by columnchromatography (PE/EA=20:1 to 5:1) to give compound 44A (200 mg, 30%).

ESI-MS: [M+H]⁺: 573

Step 2: Synthesis of 44

The solution of compound 44A (200 mg) in 90% aqueous TFA (6 mL) and TES(2 mL) was stirred at 35° C. overnight before it was concentrated underreduced pressure. The mixture was purified by prep-HPLC to give 44 (26mg, 20%) as white solid.

ESI-MS: [M−H2O+H]⁺: 265

¹H NMR (CD₃OD, 400 MHz): δ 7.293-7.273 (d, J=8.0, 1H), 6.694-6.674 (d,J=8.0, 1H), 4.387-4.330 (t, J=10, 2 H), 3.764-3.734 (t, J=6.4, J=5.6, 2H), 3.687-3.675 (d, J=5.2, 1 H), 2.731 (s, 2H), 1.040 (s, 2H)

Example 45Disodium;8-(cyclopropylmethoxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 45A

To a solution of compound 15G (0.5 g, 0.97 mmol, 1.0 eq) and Cs₂CO₃(0.947 g, 2.9 mmol, 3.0 eq) in anhydrous DMF (8 ml) was added(bromomethyl)cyclopropane (196 mg, 1.45 mmol, 1.5 eq) dropwise over 5minutes. After 2.5 hours at room temperature, the reaction mixture wasconcentrated under reduced pressure and the residue was purified byprep-TLC (PE/EA=10:1) to give compound 45A (180 mg, 33%).

ESI-MS: [MH]⁺: 571

Step 2: Synthesis of 45

To a solution of compound 45A (180 mg) in dioxane (2 mL) andconcentrated HCl (0.2 mL) was added i-BuB(OH)₂ (65 mg, 0.64 mmol, 2 eq).The mixture was stirred at room temperature for 18 hours. The reactionmixture was concentrated in vacuo, and the residue was dissolved inH₂O/MeCN. The resulting solution was adjusted to pH=12 with 1N NaOH andpurified by prep-HPLC (C18, neutral) to give 45 (31 mg, 38%) as whitesolid.

ESI-MS: [M+H]⁺: 263

¹H NMR (CD₃OD, 400 MHz): δ 6.696-6.675 (d, J=8.4, 1 H), 6.180-6.159 (d,J=8.4, 1 H), 3.774-3.757 (d, J=6.8, 2H), 2.576-2.542 (t, J=6.8, 2H),1.318-1.228 (t, J=18, 1 H), 0.507-0.485 (d, J=8.8, 2 H), 0.402-0.368 (t,J=6.8, 2 H), 0.311-0.299 (d, J=4.8, 2 H).

Example 467-(2-Amino-2-oxo-ethoxy)-2-hydroxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

Step 1: Synthesis of 46A

To a solution of compound 15G (0.5 g, 0.97 mmol, 1.0 eq) and Cs₂CO₃(0.947 g, 2.9 mmol, 3.0 eq) in anhydrous DMF (8 mL) was added ofchloroacetonitrile (147 mg, 1.94 mmol, 2.0 eq) over 5 minutes. Themixture was stirred at room temperature for 1.5 hours before it wasconcentrated under reduced pressure. The residue was purified by columnchromatography (PE/EA=5:1) to give compound 46A (0.30 g, 55.7%).

ESI-MS: [M+H]⁺: 556

Step 2: Synthesis of 46

To a solution of compound 46A (0.30 g) in dioxane (3 mL) andconcentrated HCl (0.3 mL) was added i-BuB(OH)₂ (112 mg, 1.1 mmol, 2 eq).The mixture was stirred at room temperature for 18 hours. The reactionmixture was concentrated in vacuo, and the residue was dissolved inH₂O/MeCN. The resulting solution was adjusted to pH=12 with 1N NaOH andpurified by prep-HPLC (C18, neutral) to give 46 (41 mg, 28%) as whitesolid.

ESI-MS: [M−H2O+H]⁺: 266

¹H NMR (CD₃OD, 400 MHz): δ 6.749-6.728 (d, J=8.4, 1 H), 6.148-6.127 (d,J=8.4, 1 H), 4.463 (s, 2H), 3.703-3.678 (t, J=9.6, 1 H), 3.593-3.570 (t,J=9.2, 1 H), 2.537-2.503 (t, J=6.8, 2 H), 0.419-0.392 (t, J=9.4, 2H).

Example 477-(Cyanomethoxy)-2-hydroxy-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

To a solution of compound 46A (0.32 g, 0.58 mmol, 1.0 eq) and i-BuB(OH)₂(0.836 g, 0.83 mmol, 1.5 eq) in MeOH/n-hexane (2.5 mL/2.5 mL) was addedconcentrated HCl (5 drops) dropwise. The reaction mixture was stirred at30° C. for 3 hours. The methanol layer was separated and washed withhexanes (2×). The methanol layer was then concentrated and the residuewas added DCM (2 mL) and then TFA (2.5 mL). The reaction solution wasstirred at room temperature for 2.5 hours before it was concentratedunder reduced pressure. The residue was purified by prep-HPLC (C18) togive 46 (11 mg, 8%) as white solid.

ESI-MS: [M+H]⁺: 248

¹H NMR (CD₃OD, 400 MHz): δ 7.239-7.219 (d, J=0.8, 1 H), 6.700 (d, 1H),4.974 (s, 2H), 2.736-2.398 (t, J=6.4, 2 H), 1.094-1.053 (t, J=8.0, 2 H),

Example 48Disodium;8-[2-(dimethylamino)ethoxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 48A

A solution of compound 15G (0.8 g, 1.55 mmol, 1.0 eq),N,N-dimethyl-2-chloroethylamine HCl salt (0.67 g, 4.65 mmol, 3.0 eq) andCs₂CO₃ (2.53 g, 7.75 mmol, 5.0 eq) in anhydrous DMF (15 mL) was stirredat 50° C. for 18 hours. The reaction mixture was concentrated underreduced pressure and the residue was partitioned in EA and 0.2 N HCl.The organic phase was concentrated to give crude 48A which was directlyused for next step.

ESI-MS: [M+H]⁺: 588

Step 2: Synthesis of 48

To a solution of crude compound 48A (0.8 g, 1.36 mmol, 1.0 eq) indioxane (6 mL) and concentrated (6 mL) was added i-BuB(OH)₂ (0.275 g,2.72 mmol, 2.0 eq). The mixture was stirred at room temperature for 18hours. The reaction mixture was concentrated in vacuo, and the residuewas dissolved in H₂O/MeCN. The resulting solution was adjusted to pH=12with 1N NaOH and purified by prep-HPLC (C18, neutral) to give 48 (61 mg,16%) as white solid.

ESI-MS: [M+H]⁺: 280

¹H NMR (CD3OD, 400 MHz): δ 6.788-6.766 (d, J=8.8, 1 H), 6.276-6.255 (d,J=8.4, 1 H), 4.193-40165 (t, J=11.2, 2H), 2.953 (t, 2H), 2.585-2.550 (t,J=14, 2 H), 2.513 (s, 6H), 0.478-0.445 (t, J=13.2, 2 H).

Example 49Disodium;4,4-dihydroxy-8-(hydroxymethyl)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

To a solution of 19C (150 mg, 0.28 mmol, 1.0 eq) in dioxane (2 mL) 32was added i-BuB(OH)₂ (58 mg, 0.57 mmol, 2.0 eq) and conc.HCl (2 mL). Thereaction mixture was stirred at rt for 3 hours. The reaction mixture wasconcentrated in vacuo, and the residue was dissolved in H₂O/MeCN. Theresulting solution was adjusted to pH=12 and purified by prep-HPLC (C18,neutral) to give 49 (28 mg, 40%) as white solid.

ESI-MS: [M+H]⁺: 223

¹H NMR (400 MHz, CD₃OD/H₂O): δ 7.15-7.12 (m, 1H), 6.76 (d, J=6.8 Hz,1H), 4.77 (s, 2H), 3.30 (s, 1H), 2.66-2.60 (m, 2H), 1.30-1.26 (m, 2H).

Example 50Disodium;8-(difluoromethyl)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 50A

To the solution of 19B (280 mg, 0.53 mmol, 1.0 eq) in DCM (8 mL) wasadded DAST (427 mg, 2.65 mmol, 5.0 eq) slowly at 0° C. The reactionmixture was stirred at room temperature for 16 hours. The mixture wasdiluted with DCM and washed with water. After concentration, the residuewas purified by prep-TLC to give 50A (83 mg, 20%).

ESI-MS: [M+H]⁺: 421

Step 2: Synthesis of 50

To the solution of 50A (60 mg, 0.143 mmol, 1.0 eq) in DCM (0.5 mL) wasadded TFA (0.2 mL). The resulting solution was stirred at roomtemperature for 1 hour before it was concentrated. The residue wasdissolved in H₂O/MeCN. The resulting solution was adjusted to pH=12 andpurified by prep-HPLC (C18, neutral) to give 50 (18 mg, 60%).

ESI-MS: [2M−H]⁻: 483

¹H NMR (400 MHz, CD₃OD): δ 7.65 (dt, 1H), 7.21 (d, J=7.6 Hz, 1H), 7.05(d, J=8.0 Hz, 1H), 2.72-2.66 (t, 2H), 0.96-0.91 (t, 2H).

Example 51Disodium;4,4-dihydroxy-8-(methanesulfonamido)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 51A

A mixture of 13G (700 mg, 1.29 mmol, 1.0 eq) and Pd/C (150 mg, 10%) inMeOH (7 mL) was stirred under 1 atm hydrogen atmosphere at roomtemperature for 3 hours. The mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatographyon silica (PE/EA) to give 51A (320 mg, 48%).

ESI-MS: [M+H]⁺: 516

Step 2: Synthesis of 51B

To a mixture of 51A (200 mg, 0.388 mmol, 1.0 eq) in Pyridine/DCM (3 mL/1mL) was added MsCl (106 mg, 0.931 mmol, 2.4 eq) dropwise at 0° C. Themixture was stirred at room temperature for 3 hours before it wasconcentrated in vacuo. The residue was purified by prep-TLC to give 51B(110 mg, 48%).

ESI-MS: [M+H]⁺:594

Step 3: Synthesis of 51

To a solution of 51B (100 mg, 0.169 mmol, 1.0 eq) in dioxane (2 mL) wasadded i-BuB(OH)₂ (34.2 mg, 0.338 mmol, 2.0 eq) and concentrated HCl (2mL). The reaction mixture was stirred at room temperature for 1 hour.The reaction mixture was concentrated in vacuo, and the residue wasdissolved in H₂O/MeCN. The resulting solution was adjusted to pH=12 andpurified by prep-HPLC (C18, neutral) to give 51 (22 mg, 46%) as whitesolid.

ESI-MS: [2M−H]⁻: 569

¹H NMR (400 MHz, CD₃OD): δ 6.80 (d, J=8.0 Hz, 1H), 6.68 (d, J=8.0 Hz,1H), 2.84 (s, 3H), 2.62-2.58 (m, 2H), 0.48-0.43 (m, 2H).

Example 52Disodium;4,4-dihydroxy-8-(sulfamoylamino)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 52A

To a mixture of 51A (130 mg, 0.252 mmol, 1.0 eq) in pyridine (3 mL) wasadded ClSO₂NHBoc (81.3 mg, 0.378 mmol, 1.5 eq) at 0° C., The mixture wasstirred at room temperature for 1 hour before it was concentrated invacuo. The residue was purified by prep-TLC to give 52A (100 mg, 57%).

ESI-MS: [M+H]⁺: 695

Step 2: Synthesis of 52

To a solution of 52A (80 mg, 0.115 mmol, 1.0 eq) in dioxane (2 mL) wasadded i-BuB(OH)₂ (23.3 mg, 0.23 mmol, 2.0 eq) and concentrated HCl (1mL). The reaction mixture was stirred at rt for 1 hour. The reactionmixture was concentrated in vacuo, and the residue was dissolved inH₂O/MeCN. The resulting solution was adjusted to pH=12 and purified byprep-HPLC (C18, neutral) to give 52 (10 mg, 30%).

ESI-MS: [2M−H]⁻: 571

¹H NMR (400 MHz, CD₃OD): δ 6.75 (d, J=7.6 Hz, 1H), 2.59-2.55 (m, 2H),2.04-2.03 (m, 2H), 0.48-0.44 (m, 2H).

Example 53Trisodium;4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7,8-dicarboxylate

Step 1: Synthesis of 53A

A solution of compound 19B (330 mg, 0.624 mmol, 1.0 eq), NaClO₂ (113 mg,1.25 mmol, 2 eq) and NH₂SO₃H (122 mg, 1.25 mmol, 2 eq) in dioxane/H₂O (9mL/3 mL) was stirred at 0° C. for 2 hours. The reaction solution wasconcentrated under reduced pressure and the residue was purified bycolumn chromatography (PE/EA=1:1) to give compound 53A (200 mg, 63%).

ESI-MS: [M+H]⁺:545

Step 2: Synthesis of 53

To a solution of compound 53A (200 mg) and i-BuB(OH)₂ (75 mg, 0.73 mmol,2 eq) in dioxane (3 mL) was added concentrated HCl (3 mL) at roomtemperature. The reaction mixture was stirred at rt for 1 hour. Thereaction mixture was concentrated in vacuo, and the residue wasdissolved in H₂O/MeCN. The resulting solution was adjusted to pH=12 andpurified by prep-HPLC (C18, neutral) to give 53 (11 mg, 10%) as whitesolid.

ESI-MS: [M+H]⁺: 237

¹H NMR (CD₃OD, 400 MHz): δ 7.021-7.003 (d, J=7.2, 1 H), 6.810-6.791 (d,J=7.6, 1 H), 2.647-2.614 (t, J=6.6, 2 H), 0.524-0.491 (t, J=7.0, 2 H)

Example 54Disodium;8-cyano-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 54A

To a solution of compound 19B (1.0 g, 1.89 mmol, 1.0 eq) in ethanol (15mL) was added hydroxylamine (160 mg, 2.84 mmol, 1.5 eq). The mixture wasstirred at room temperature for 2 hours before it was concentrated underreduced pressure. The crude product 54A (1.01 g) was used directly fornext step.

ESI-MS: [M+H]⁺: 544

Step 2: Synthesis of 54B

To a solution of compound 54A (1.01 g, 1.86 mmol, 1.0 eq) and PPh₃ (1.07g, 4.1 mmol, 2.2 eq) in DCM (20 mL) was added I₂ (1.04 g, 4.1 mmol, 2.2eq) at room temperature. The mixture was stirred at 40° C. overnightbefore it was concentrated under reduced pressure. The residue waspurified by column chromatography (PE/EA=30:1 to 7:1) to give compound54B (55 mg, 7%).

ESI-MS: [M+H]⁺: 526

Step 3: Synthesis of 54

To a solution of the compound 54B (55 mg) in dioxane (2 mL) andconcentrated HCl (2 mL) was added i-BuB(OH)₂ (22 mg, 0.21 mmol, 2.0 eq).The reaction mixture was stirred at rt for 1 hour. The reaction mixturewas concentrated in vacuo, and the residue was dissolved in H₂O/MeCN.The resulting solution was adjusted to pH=12 and purified by prep-HPLC(C18, neutral) to give 54 (7 mg, 20%) as white solid.

ESI-MS: [M+H]⁺: 218

¹H NMR (CD₃OD, 400 MHz): δ 7.281-7.263 (d, J=7.2, 1H), 6.992-6.975 (d,J=6.8, 1H), 2.724-2.706 (t, 2H), 2.220-2.183 (t, 2H), 2.015-1.998 (t,2H), 0.897-0.863 (t, 2H), 0.510-0.486 (t, 2H).

Example 55Disodium;4,4-dihydroxy-8-(methoxyiminomethyl)-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 55A

To the solution of compound 19B (300 mg, 0.57 mmol, 1.0 eq) in ethanol(10 mL) was added methoxyamine hydrochloride salt. After 2 hours at roomtemperature, the reaction mixture was concentrated under reducedpressure. The crude intermediate 55A (300 mg) was used directly for nextstep without purification.

ESI-MS: [M+H]⁺: 558

Step 2: Synthesis of 55

To a solution of the crude 55A (300 mg) in dioxane (5 mL) andconcentrated HCl (1 mL) was added i-BuB(OH)₂ (82 mg, 0.81 mmol, 1.5 eq).The reaction mixture was stirred at rt for 1 hour. The reaction mixturewas concentrated in vacuo, and the residue was dissolved in H₂O/MeCN.The resulting solution was adjusted to pH=12 and purified by prep-HPLC(C18, neutral) to give 55 (15 mg, 20%) as white solid.

ESI-MS: [M+H]⁺: 250

Example 56Disodium;8-(difluoromethoxy)-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 56B

A solution of compound 56A (prepared from 15C using procedure as in step6 of Example 15) (6.00 g, 15.4 mmol, 1.0 eq) and potassium carbonate(2.13 g, 15.4 mmol, 1.0 eq) in anhydrous DMF (15 mL) was cooled to −78°C. and bubbled with bromodifluoromethane (˜6 g, ˜3 eq). The reactionmixture was warmed up and then heated up to 80° C. After 2.5 hours, themixture was cooled down and partitioned in ethyl acetate and 0.1 Naqueous HCl. The organic layer was washed with water (2×10 mL) and driedover Na₂SO₄. The solvent was removed under reduced pressure, and theresidue was purified by column chromatography (hexanes/EtOAc=15:1) togive compound 56B (2.2 g, 32%) as slight yellow oil.

H NMR (CDCl₃, 300 MHz): δ7.60 (d, 1H), 7.01 (d, 1H), 6.49 (t, 1H), 1.56(s, 18H).

Step 2: Synthesis of 56C

The mixture of compound 56B (600 mg, 1.37 mmol, 1.0 eq), potassiumvinyltrifluoroborate (457 mg, 3.43 mmol, 2.5 eq), PdCl₂ (dppf) (57 mg,0.07 mmol, 0.05 eq) and triethylamine (0.27 mL, 2.06 mmol, 1.5 eq) in2-propanol (25 mL) was degassed and filled with N₂ (3×), then was heatedto reflux. After refluxing for 18 hours, the mixture was cooled down andfiltered. The solution was concentrated under reduced pressure, and theresidue was purified by column chromatography (hexanes/EtOAc=6:1) togive compound 56C (478 mg, 90%) as slight yellow solid. HNMR (CDCl₃, 300MHz): δ7.55 (d, 1H), 7.15 (d, 1H), 6.72 (dd, 1H), 6.50 (t, 1H), 5.75 (d,1H), 5.39 (d, 1H), 1.56 (s, 18H).

Step 3: Synthesis of 56D

The catalyst [IrCl(cod)]₂ (16 mg, 0.025 mmol, 0.02 eq) and ligand dppe(20 mg, 0.049 mmol, 0.04 eq) were dissolved in dichloromethane (4 mL)under N₂ atmosphere and stirred at room temperature. After 5 minutes,pinBH (0.23 mL, 1.49 mmol, 1.2 eq) and the solution of compound 56C (478mg, 1.24 mmol, 1.0 eq) were added under N₂ atmosphere. After stirring atroom temperature for 18 hours, the reaction mixture was concentratedunder reduced pressure, and the residue was purified by columnchromatography (hexanes/EtOAc=10:1) to give compound 56D (315 mg, 49%)as slight yellow solid.

ESI-MS: [M+H]⁺: 515

Step 4: Synthesis of 56

To the mixture of compound 56D (315 mg, 0.612 mmol, 1.0 eq) andtriethylsilane (712 mg, 6.12 mmol, 10 eq) was added TFA (5 mL) at roomtemperature. After 3 hours, the mixture was concentrated andre-dissolved in MeCN/H₂O (5 mL, 1/1, v/v) and adjusted to PH=9 with 1 NNaOH solution. The solution was stirred at room temperature for 20 hoursand then purified by prep-HPLC (C18, neutral) to give 56 Na salt (43 mg)as white solid.

H NMR (D₂O, 300 MHz): δ6.83 (d, J=8.4 Hz, 1H), 6.50 (t, J=74.7 Hz, 1H),6.36 (d, J=8.4 Hz, 1H), 2.47 (t, J=7.5 Hz, 2H), 0.37 (t, J=7.2 Hz, 2H).

ESI-MS: [2M−H]⁻: 515

Example 57Disodium;8-ethoxy-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 57A

To the solution of compound 56A (1.0 g, 2.6 mmol, 1.0 eq) and potassiumcarbonate (524 mg, 3.8 mmol, 1.5 eq) in anhydrous DMF (15 mL) was addediodoethane (2.1 mL, 26 mmol, 10 eq). After 18 hours at room temperature,the reaction mixture was partitioned in ethyl acetate and 0.1 N aqueousHCl. The organic layer was washed with water (2×) and dried over Na₂SO₄.The solvent was removed under reduced pressure, and the residue waspurified by column chromatography (hexanes/EtOAc=20:1 to 5/1) to givecompound 57A (1.06 g, 98%) as slight yellow oil.

¹H NMR (CDCl₃, 300 MHz): δ7.48 (d, J=9.0 Hz, 1H), 6.68 (d, J=9.0 Hz,1H), 4.03 (q, J=7.2 Hz, 2H), 1.56 (s, 18H), 1.38 (t, J=7.2 Hz, 3H).

Step 2: Synthesis of 57B

To the mixture of Zn powder (830 mg, 12.7 mmol, 5.0 eq) and 7E (55 mg,0.2 mmol) in anhydrous THF (2.0 mL) was added DIBAL-H (0.26 mL, 0.26mmol, 1.0 M in hexanes, 0.05 eq) at room temperature. The mixture wasstirred at 30° C. for 5 min, then more (+)-pinanediolboratemethylenebromide (1.38 g, 5.0 mmol, 2.0 eq) in anhydrous THF (3.0 mL)was added drop-wise into the mixture over 10 minutes. The reactionmixture was stirred at 50° C. for 2 hours before it was cooled to roomtemperature and settled down. The top clear solution was transferredinto a mixture of compound 57A (1.06 g, 2.5 mmol, 1.0 eq) andPd(t-Bu₃P)₂ (64 mg, 0.13 mmol, 0.05 eq) in THF (10 mL) under N₂atmosphere. The mixture was stirred at room temperature for 2.5 hoursbefore it was concentrated in vacuo. The obtained residue was purifiedby column chromatography (hexanes/EtOAc=10:1 to 5/1) to give compound57B (1.25 g, 97%) as slight yellow oil.

ESI-MS: [M+H]⁺: 531

Step 3: Synthesis of 57C

To the solution of compound 57B (320 mg, 0.61 mmol, 1.0 eq) andchloroiodomethane (0.09 mL, 1.2 mmol, 2.0 eq) in THF (2.0 mL) was addedn-BuLi (0.36 mL, 2.5 M in hexanes, 0.9 mmol, 1.5 eq) slowly at −78° C.under N₂ atmosphere. The resulting solution was slowly warmed up to roomtemperature in 18 hours before it was concentrated under reducedpressure. The obtained residue was purified by column chromatography(hexanes/EtOAc=10:1) to give compound 57C (250 mg, 76%) as slight yellowoil.

ESI-MS: [M+H]⁺: 545

Step 4: Synthesis of 57

To the mixture of compound 57C (75 mg, 0.14 mmol, 1.0 eq) and i-BuB(OH)₂(42 mg, 0.42 mmol, 3.0 eq) in hexanes (3.0 mL) and MeOH (3.0 mL) wasadded concentrated HCl (2 drops) at room temperature. After 20 hours,the two layers were separated and the MeOH layer was washed with hexanes(2×). The MeOH layer was concentrated and was added triethylsilane (162mg, 1.4 mmol, 10 eq) and TFA (3 mL) at room temperature. After 3 hours,the reaction mixture was concentrated and re-dissolved in MeCN/H₂O (5mL, 1/1, v/v) and adjusted to PH=10 with 1 N NaOH solution. The solutionwas stirred at room temperature for 20 hours and then purified byprep-HPLC (C18, neutral) to give 57 Na salt (31 mg) as white solid.

¹H NMR (D₂O, 300 MHz): δ6.67 (d, J=8.1 Hz, 1H), 6.15 (d, J=8.4 Hz, 1H),3.98 (q, 2H), 2.55 (t, 2H), 1.31 (t, 3H), 0.42 (t, 2H).

ESI-MS: [M−H₂O+H]⁺: 219

Example 588-Fluoro-2-hydroxy-3,5-dihydro-1,4,2-benzodioxaborepine-9-carboxylicacid

Step 1: Synthesis of 58B

The mixture of compound 58A (prepared from of 36A (WO 15179308) viahydrolysis as in synthesis of 36D and acetonide formation as in 7J) (4.4g, 16 mmol, 1.0 eq), potassium vinyltrifluoroborate (3.2 g, 24 mol, 1.5eq), TEA (4.86 g, 48 mol, 3.0 eq) and PdCl₂ (dppf) (653 mg, 0.8 mmol,0.05 eq) in dioxane (30 mL) was stirred at 100° C. for 12 hours under N₂atmosphere. The mixture was concentrated and purified by columnchromatography (hexanes/EtOAc=5:1 to 1/1) to give compound 58B (1.6 g,45% yield) as yellow solid.

Step 2: Synthesis of 58C

To a solution of compound 58B (1.6 g, 7.2 mmol, 1.0 eq) in DCM (30 mL)was bubbled with O₃ at −78° C. until the solution turned to slightlyblue. The nitrogen was bubbled in to remove the color. The colorlesssolution was added dimethylsulfide (3 mL) and slowly warmed up to roomtemperature in 6 hours. The solvent was removed under reduced pressureand the residue was purified by column chromatography (PE/EA=3:1) togive compound 58C (1.0 g, 62%) as yellow oil.

Step 3: Synthesis of 58D

To a solution of compound 58C (1.0 g, 4.46 mmol, 1.0 eq) in anhydrousTHF (20 mL) was added NaBH₄ (254 mg, 6.7 mmol, 1.5 eq) at 0° C. Themixture was stirred at room temperature for 1 hour before it wasquenched with water. The reaction mixture was concentrated under reducedpressure, and the residue was purified by column chromatography(PE/EA=1:1) to give compound 58D (650 mg, 64%) as yellow solid.

¹H NMR (CDCl₃, 400 MHz): δ7.62 (dd, 1H), 6.85 (dd, 1H), 4.66 (s, 2H),1.76 (s, 6H).

Step 4: Synthesis of 58E

To the solution of compound 58D (192 mg, 0.85 mmol, 1.0 eq) in anhydrousTHF (4 mL) was added a suspension of NaH (51 mg, 60% in mineral oil,1.28 mmol, 1.5 eq) in THF (2 mL) dropwise at 0° C. under nitrogenatmosphere. After 10 minutes, a solution of (+)-pinanediolboratemethylenebromide (464 mg, 1.7 mmol, 2.0 eq) in THF (4 mL) was added intoabove solution and the reaction mixture was slowly heated up to 50° C.After 3 hours, the reaction was quenched with saturated aqueous NH₄Cland extracted with ethyl acetate. The organic layer was dried overNa₂SO₄. The solvent was removed under reduced pressure, and the residuewas purified by column chromatography (hexanes/EtOAc=20:1 to 5/1) togive compound 58E (102 mg, 29%) as colorless oil.

ESI-MS: [M+H]⁺: 419

Step 2: Synthesis of 58

The mixture of compound 58E (85 mg, 0.20 mmol, 1.0 eq) in dioxane (0.5mL) and 3N NaOH (0.5 mL) was stirred at room temperature for 2 hours,LCMS indicating the disappearance of starting material. To this mixturewas then added 5N HCl (0.7 mL) and i-BuB(OH)₂ (61 mg, 0.6 mmol, 3.0 eq).After overnight at room temperature, the reaction mixture wasconcentrated in vacuo and the residue was purified by prep-HPLC (C18,acetonitrile and water as mobile phases, 0.1% HCOOH) to give 58 (8.7 mg)as white solid.

¹H NMR (CD₃OD, 300 MHz): δ7.53 (dd, 1H), 6.64 (dd, 1H), 4.48 (s, 2H),3.30 (s, 2H).

ESI-MS: [3M-2H₂O—H]⁻: 641

Example 59Disodium;4,4-dihydroxy-5-oxa-9-aza-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 59B

To the solution of compound 59A (J. Med. Chem., 2008, 51, 5330-41) (2.9g, 13.3 mmol, 1.0 eq) in TFAA (6 mL) and TFA (12 mL) was added acetone(5 mL) dropwise at room temperature. After 1 hour, the reaction mixturewas added DMF (15 mL) to give a clear brown solution, followed by moreacetone (5 mL). After stirred at room temperature for 18 hours, themixture was concentrated in vacuo and the residue was partitioned inEtOAc/hexanes (3/1, v/v) and saturated NaHCO₃. The organic layer waswashed with water (2×) and dried over Na₂SO₄. The solvent was removedunder reduced pressure, and the residue was purified by columnchromatography (hexanes/EtOAc=3:1 to 0/1) to give compound 59B (2.1 g,61%) as yellow solid.

¹H NMR (CDCl₃, 300 MHz): δ8.99 (s, 1H), 8.80 (s, 1H), 1.83 (s, 6H).

Step 2: Synthesis of 59C

The mixture of compound 59B (820 mg, 3.18 mmol, 1.0 eq), potassiumvinyltrifluoroborate (554 mg, 4.13 mmol, 1.3 eq), PdCl₂ (dppf) (130 mg,0.16 mmol, 0.05 eq) and triethylamine (0.89 mL, 6.4 mmol, 2 eq) in2-propanol (30 mL) was degassed and filled with N₂ (3×), then was heatedto reflux. After refluxing for 20 hours, the mixture was cooled down andfiltered. The solution was concentrated under reduced pressure, and theresidue was purified by column chromatography (hexanes/EtOAc=3/1 to 1/1)to give compound 59C (517 mg, 79%) as slight yellow solid.

¹H NMR (CDCl₃, 300 MHz): δ8.97 (s, 1H), 8.74 (s, 1H), 6.76 (dd, 1H),5.95 (d, J=18.0 Hz, 1H), 5.50 (d, J=11.4 Hz, 1H), 1.78 (s, 6H).

Step 3: Synthesis of 59D

The catalyst [IrCl(cod)]₂ (24 mg, 0.036 mmol, 0.03 eq) and ligand dppe(29 mg, 0.073 mmol, 0.06 eq) were dissolved in dichloromethane (4 mL)under N₂ atmosphere and stirred at room temperature. After 5 minutes,pinBH (0.21 mL, 1.44 mmol, 1.2 eq) and compound 59C (246 mg, 1.2 mmol,1.0 eq) were added, and the solution was flushed with N₂ again. Afterstirring at room temperature for 18 hours, the reaction mixture wasconcentrated under reduced pressure, and the residue was purified bycolumn chromatography (hexanes/EtOAc=3/1 to 1/1) to give compound 59D(82 mg, 21%) as slight yellow solid.

ESI-MS: [M+H]⁺: 334

Step 4: Synthesis of 59

The mixture of compound 59D (82 mg, 0.24 mmol, 1.0 eq) in dioxane (0.5mL) and 3N NaOH (0.5 mL) was stirred at room temperature for 2 hours,LCMS indicating the disappearance of starting material. The reactionmixture was concentrated in vacuo and the residue was purified byprep-HPLC (C18, acetonitrile and water as mobile phases, neutral) togive 59 Na salt (8.0 mg) as off-white solid.

¹H NMR (D₂O, 300 MHz): δ8.05 (s, 1H), 7.86 (s, 1H), 2.59 (t, J=7.2 Hz,2H), 0.41 (t, J=7.2 Hz, 2H).

ESI-MS: [M+H]⁺: 194

Example 60Disodium;3,3-dideuterio-4,4-dihydroxy-8-methoxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(10),6,8-triene-7-carboxylate

Step 1: Synthesis of 60B

To the solution of PPh₃CD₃I (896 mg, 2.2 mmol, 1.1 eq) in THF (15 mL)was added n-BuLi (0.84 mL, 2.5 M in hexanes, 2.1 mmol, 1.05 eq) dropwisein 5 minutes at −78° C. After 1 hour, compound 60A (473 mg, 2.0 mmol,1.0 eq) in THF (8 mL) was slowly added into above reaction mixture. Thereaction mixture was slowly warmed up to room temperature and stirredfor 1 hour. The mixture was quenched with saturated NH₄Cl and extractedwith EtOAc (2×). The organic layer was concentrated in vacuo and theresidue was purified by column chromatography (hexanes/EtOAc=3:1 to 1/1)to give compound 60B (170 mg, 36%) as white solid.

¹H NMR (CDCl₃, 300 MHz): δ7.65 (d, J=9.0 Hz, 1H), 6.80 (s, 1H), 6.64 (d,J=9.0 Hz, 1H), 3.97 (s, 3H), 1.73 (s, 6H).

Step 2: Synthesis of 60C

The mixture of compound 60B (155 mg, 0.66 mmol, 1.0 eq),bis(pinacolato)diboron (192 mg, 0.76 mmol, 1.15 eq) and PPh₃ (19 mg,0.07 mmol, 0.11 eq) in methanol (2 mL) was added K₂HP₄ (137 mg, 0.79mmol, 1.2 eq), and then Cu₂O (7.5 mg, 0.05 mmol, 0.08 eq). The resultingmixture was flushed with nitrogen and stirred at 40° C. for 6 hoursbefore it was partitioned in EtOAc and 0.1 M K₂HP₄. The organic layerwas washed with 0.1 M K₂HP₄ and dried over Na₂SO₄. The solution wasconcentrated under reduced pressure, and the residue was purified bycolumn chromatography (hexanes/EtOAc=3/1 to 1/1) to give compound 60D(191 mg, 80%) as white crystal.

ESI-MS: [M+H]⁺: 365

Step 3: Synthesis of 60

The mixture of compound 60D (65 mg, 0.18 mmol, 1.0 eq) in dioxane (0.4mL) and 3N NaOH (0.4 mL) was stirred at room temperature for 2 hours,LCMS indicating the disappearance of starting material. The reactionmixture was concentrated in vacuo and the residue was purified byprep-HPLC (C18, acetonitrile and water as mobile phases, 0.1% HCOOH).The obtained solid was dissolved in MeCN/H₂O and was adjusted to PH=8with 0.1 N NaOH. Sodium salt of 60 was obtained as white solid (11 mg)after lyophilization.

¹H NMR (D₂O, 300 MHz): δ6.78 (d, J=8.4 Hz, 1H), 6.22 (d, J=8.4 Hz, 1H),3.59 (s, 3H), 2.43 (s, 2H).

ESI-MS: [M−H2O+H]⁺: 207

Example 61 Disodium;8-carbamoyl-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 61A

To a solution of compound 19B (300 mg, 0.57 mmol, 1.0 eq) in ethanol(8.0 mL) was added hydroxyamine HCl salt (60 mg, 0.85 mmol, 1.5 eq). Themixture was stirred at room temperature for 2 hours before it wasconcentrated under reduced pressure. The residue was purified byprep-TLC to give compound 61A (200 mg, 65%).

ESI-MS: [M+H]⁺: 544

Step 2: Synthesis of 61

To a solution of compound 61A (200 mg, 0.37 mmol, 1.0 eq) in dioxane (2mL) was added i-BuB(OH)₂ (75 mg, 0.74 mmol, 2.0 eq) and concentrated HCl(2 mL). The reaction mixture was stirred at room temperature for 3hours. The reaction mixture was concentrated in vacuo, and the residuewas dissolved in H₂O/MeCN. The resulting solution was adjusted to pH=10with 1N NaOH and purified by prep-HPLC (C18, neutral) to give 61 Na salt(11 mg, 12%) as white solid.

ESI-MS: [M+H]⁺: 236

¹H NMR (400 MHz, CD₃OD): δ 6.94 (d, J=7.6 Hz, 1H), 6.84 (d, J=7.6 Hz,1H), 2.68-2.64 (m, 2H), 0.53-0.48 (m, 2H).

Example 62Disodium;8-[4-(azetidin-1-yl)but-2-ynoxy]-4,4-dihydroxy-5-oxa-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 62A

To a solution of compound 15G (1.0 g, 1.9 mmol, 1.0 eq) in DMF (15 mL)was added 1,4-dichlorobut-2-yne (490 mg, 4.0 mmol, 2.0 eq), K₂CO₃ (800mg, 5.8 mmol, 3.0 eq) and NaI (290 mg, 1.9 mmol, 1.0 eq). The mixturewas stirred at 80° C. for 3 hours before it was concentrated underreduced pressure. The residue was purified by column chromatography(hexanes/EtOAc=10/1 to 5/1) to give compound 62A (900 mg, 77%).

ESI-MS: [M+H]⁺: 603

Step 2: Synthesis of 62B

To a solution of compound 62A (500 mg, 0.83 mmol, 1.0 eq) in DMF (10 mL)was added azetidine (95 mg, 1.66 mmol, 2.0 eq) and K₂CO₃ (458 mg, 3.3mmol, 4.0 eq). The mixture was stirred at 50° C. for 2 before it wasconcentrated under reduced pressure. The residue was purified by columnchromatography (hexanes/EtOAc=10/1 to 3/1) to give compound 62B (220 mg,43%).

ESI-MS: [M+H]⁺: 524

Step 3: Synthesis of 62

The mixture of compound 62B (200 mg, 0.38 mmol, 1.0 eq), TES (0.5 mL)and i-BuB(OH)₂ (5 mg, 49 mmol, 2.0 eq) in 90% aqueous TFA (1 mL) wasstirred at room temperature for half hour before it was concentrated invacuo. The residue was dissolved in water/MeCN and adjusted to PH=12with 1N NaOH. The solution was purified by prep-HPLC (C18, neutral) togive 62 sodium salt (56 mg, 51%) as white solid.

ESI-MS: [M+H]⁺: 316

¹H NMR (400 MHz, CD₃OD): δ 6.69 (d, J=8.4 Hz, 1H), 6.34 (d, J=8.4 Hz,1H), 4.68 (s, 2H), 3.31-3.29 (m, 4H), 3.27-3.25 (m, 2H), 2.58-2.53 (m,2H), 2.07-2.02 (m, 2H), 0.44-0.42 (m, 2H).

Example 63Disodium;4,4-dihydroxy-8-methoxy-5-oxa-9-aza-4-boranuidabicyclo[4.4.0]deca-1(6),7,9-triene-7-carboxylate

Step 1: Synthesis of 63B

To a solution of compound 63A (10 g, 68 mmol, 1.0 eq) in dry THF (50 mL)was added freshly made LDA (121.6 mmol, in 60 mL THF, 1.8 eq) at −78° C.The mixture was stirred at −78° C. for half hour before bubbled with dryCO₂ gas. The resulting mixture was slowly warmed up to room temperatureand quenched with 1N HCl. The mixture was extracted with EA, and theorganic layer was dried over Na₂SO₄. After concentration under reducedpressure, compound 63B (12.8 g, 97%) was obtained as off-white solidwithout further purification.

Step 2: Synthesis of 63C

To a solution of compound 63B (1.0 g, 5.2 mmol, 1.0 eq) in dry THF (6.0mL) was added tert-butyl 2,2,2-trichloroacetimidate (1.6 ml, 8.9 mmol,1.7 eq) and BF₃-Et₂O (0.034 ml, 0.26 mmol, 0.05 eq) at 0° C. Thereaction solution was stirred at room temperature for 2 hours undernitrogen atmosphere before it was quenched with saturated aqueousNaHCO₃. The mixture was extracted with EA and the organic layer wasdried over Na₂SO₄. After concentration under reduced pressure, compound63C (1.44 g, 99%) was obtained as light yellow oil, which was used fornext step without further purification.

Step 3: Synthesis of 63D

To a solution of compound 63C (12.2 g, 49.5 mmol, 1.0 eq) in DMF (20 mL)was added BnOH (5.14 ml, 49.5 mmol, 1.0 eq) at 0° C., followed by NaH(2.6 g, 64.4 mmol, 1.3 q). The mixture was stirred at 0° C. for halfhour under nitrogen atmosphere before it was quenched with water. Themixture was extracted with PE/EA (1:1) and dried over Na₂SO₄. Afterconcentration under reduced pressure, compound 63D (7.1 g, 50%) wasobtained as yellow oil, which was used for next step without furtherpurification.

Step 4: Synthesis of 63E

The suspension of compound 63D (4.2 g, 1.47 mmol, 1.0 eq) and Pd/C (200mg, 10%) in dry THF/MeOH (20 mL/10 mL) was stirred at room temperaturefor 4 hours under 1 atm hydrogen atmosphere. The reaction mixture wasfiltered and the filtrate was concentrated and purified by columnchromatography (PE/EA=5:1 to 1:1) to give compound 63E (3.3 g, 98%).

Step 5: Synthesis of 63F

To a solution of compound 63E (1.5 g, 6.22 mmol, 1.0 eq) in CHCl₃ (5 mL)at 0° C. was added NBS (1.22 g, 6.85 mmol, 1.1 eq). The mixture wasstirred at room temperature for 2 hours before it was concentrated. Theresidue was triturated with PE/EA (20:1). After filtration, the filtratewas concentrated to give compound 63F (1.98 g, 98%), which was directlyused for next step without further purification.

Step 6: Synthesis of 63G

To a solution of compound 63F (1.2 g, 2.93 mmol, 1.0 eq) in DMF (10 mL)was added Cs₂CO₃ (607 mg, 4.4 mmol, 1.5 eq) and BnBr (0.52 mL, 4.4 mmol,1.5 eq). The mixture was stirred at room temperature for 2 hours beforeit was concentrated. The residue was purified by column chromatography(hexanes/EtOAc=20/1 to 5/1) to give compound 63G (1.0 g, 64%).

Step 7: Synthesis of 63H

To a solution of compound 63G (2.37 g, 5.97 mmol, 1.0 eq) in MeOH (20mL) was added MeONa (645 mg, 11.9 mmol, 2.0 eq). The mixture was stirredat room temperature for 16 hours before it was concentrated. The residuewas purified by column chromatography (hexanes/EtOAc=10/1) to givecompound 63H (926 mg, 39%).

Step 8: Synthesis of 63I

To a solution of compound 63H (926 mg, 2.36 mmol, 1.0 eq) in dioxane/H₂O(12 mL/1.5 mL) was added potassium vinyltrifluoroborate (631 mg, 4.71mmol, 2.0 eq), Cs₂CO₃ (2.3 g, 7.07 mmol, 3.0 eq) and PdCl₂ (dppf) (154mg, 0.18 mmol, 0.08 eq). The mixture was stirred at 100° C. for 3 hoursunder hydrogen atmosphere. The resulting mixture was filtered and thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography (hexanes/EtOAc=4/1 to 2/1) to give compound 631 (408 mg,50%).

Step 9: Synthesis of 63J

To a solution of compound 631 (100 mg, 0.3 mmol, 1.0 eq) indichloromethane (10 mL) was added4,4,5,5-tetramethyl-1,3,2-dioxaborolane (75 mg, 0.6 mmol, 2.0 eq),[IrCl(COD)]₂ (6 mg, 0.01 mmol, 0.03 eq) and dppe (7 mg, 0.02 mmol, 0.06eq). The mixture was stirred at 30° C. for 12 hours under hydrogenatmosphere. The resulting mixture was concentrated under reducedpressure to give crude compound 63J (120 mg) which was used directly forthe next step without further purification.

ESI-MS: [M+H]⁺: 470

Step 10: Synthesis of 63K

The solution of crude compound 63J (210 mg, 0.45 mmol, 1.0 eq) and(+)-pinanediol (114 mg, 0.67 mmol, 1.5 eq) in THF (5 mL) was stirred atroom temperature for 12 hours. The resulting mixture was concentratedand the residue was purified by prep-TLC (hexanes/EtOAc=4/1) to givecompound 63K (80 mg, 28%).

ESI-MS: [M+H]⁺: 522

Step 11: Synthesis of 63L

The suspension of compound 63K (75 mg, 0.14 mmol, 1.0 eq) and Pd/C (20mg, 10%) in EtOAc (2 mL) was stirred at room temperature for 12 hoursunder 1 atm hydrogen atmosphere. The mixture was filtered andconcentrated to give compound 63L (35 mg, 56%).

ESI-MS: [M+H]⁺: 432

Step 12: Synthesis of 63

To the mixture of compound 63L (35 mg, 0.08 mmol, 1.0 eq) and TES (1 mL)in TFA (90% aqueous, 3 mL) was added i-BuB(OH)₂ (17 mg, 0.16 mmol, 2eq). The mixture was stirred at room temperature for 1 hour before itwas concentrated to dryness. The residue was dissolved in H₂O/MeCN andwas adjusted to PH=12 with 1N NaOH. The resulting solution was purifiedby prep-HPLC (C18, neutral) to give 63 Na salt (8 mg, 44%) as whitesolid.

ESI-MS: [M+H]⁺: 242

¹H NMR (400 MHz, CD₃OD): δ 7.47 (s, 1H), 3.81 (s, 3H), 2.62-2.50 (m,2H), 0.53-0.45 (m, 2H).

Example 642-Hydroxy-7-[(1,3,4-thiadiazol-2-ylamino)methyl]-3,4-dihydro-1,2-benzoxaborinine-8-carboxylicacid

Step 1: Synthesis of 64A

The mixture of compound 19B (500 mg, 0.95 mmol, 1.0 eq), 4A molecularsieves (250 mg), AcOH (0.3 mL) and 1,3,4-thiadiazol-2-amine (240 mg, 2.4mmol, 2.5 eq) in DCE (10 mL) was stirred at room temperature for 1 hourbefore NaBH(OAc)₃ (403 mg, 1.9 mmol, 2 eq) was added. The mixture wasstirred at 70° C. for 12 hours before it was filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography (hexanes/EtOAc=4/1 to 2/1) to give compound 64A (150 mg,26%).

ESI-MS: [M+H]⁺: 614

Step 2: Synthesis of 64

To a solution of compound 64A (110 mg, 0.18 mmol, 1.0 eq) and TES (1 mL)in TFA (90% aqueous, 3 mL) was added i-BuB(OH)₂ (38 mg, 0.37 mmol, 2eq). The mixture was stirred at room temperature for 2 hours before itwas concentrated to dryness. The residue was purified by prep-HPLC (C18,0.1% HCOOH) to give 64 (13 mg, 24%) as white solid.

ESI-MS: [M+H]⁺: 306

¹H NMR (400 MHz, CD₃OD): δ 8.62 (d, J=14 Hz, 1H), 7.29-7.24 (m, 1H),6.92-6.85 (m, 1H), 4.84-4.72 (m, 2H), 3.31-3.25 (m, 2H), 0.74-0.70 (m,2H).

Example 65. Potentiation of Aztreonam

The potency and spectrum of β-lactamase inhibitors (BLIs) was determinedby assessing their aztreonam potentiation activity in a dose titrationpotentiation assay using strains of various bacteria that are resistantto aztreonam due to expression of various β-lactamases. Aztreonam is amonobactam antibiotic and is hydrolyzed by the majority ofbeta-lactamases that belong to class A or C (but not class B or D). Thepotentiation effect was observed as the ability of BLI compounds toinhibit growth in the presence of sub-inhibitory concentration ofaztreonam. MICs of test strains varied from 64 μg/mL to >128 μg/mL.Aztreonam was present in the test medium at 4 μg/mL. Compounds weretested at concentrations up to 40 μg/mL. In this assay, potency ofcompounds was reported as the minimum concentration of BLI required toinhibit growth of bacteria in the presence of 4 μg/mL of aztreonam(MPC_(@4)). Table 1B summarizes the BLI potency of aztreonampotentiation (MPC_(@4)) for various strains overexpressing class A (ESBLand KPC), and class C beta-lactamases. Aztreonam MIC for each strain isalso shown.

TABLE 1 Activity of BLIs to potentiate aztreonam against strainsexpressing class A and class C enzymes. Aztreonam MIC (μg/mL) >128 >12864 128 AZT AZT >128 AZT AZT >128 >128 MPC4 MPC4 AZT MPC4 MPC4 AZT 64 AZTCTX- CTX- MPC4 SHV- TEM- MPC4 AZT MPC4 M-14 M-15 SHV-5 12 10 KPC-2 MPC4CMY-6 Compound KP1005 KP1009 ec308 KP1010 ec302 KP1004 ECL1002 EC1010 1X X X X X X Y X 2 X X X X X X X X 3 X X X X X X X X 4 Z Z Z Z Z Z Z Z 5Z Y Z Y Z X Z Y 6 X X Y X X X X X 7 X X X X X X X X 8 X X X X X X X X 9Z Z Y Y Z X Y Y 10 Z Z Z Y Z Y Z Z 11 Y Y Y Y Y Y Y X 12 Z Y Y Y Z Y Y Y13 X X X X X X X X 14 Y Y Y X Y X Z Y 15 Y X X X X X X X 16 X X Y X X XX X 17 Z Z Z Y Z X Z Y 18 Y X X X X X X X 19 Y X X X Y X Y X 20 Y X X XX X X X 21 Y Y Y X Y X Y X 22 Z Y Y X X X Y X 23 Y X Y X X X X X 24 X XX X X X X X 25 Y X X X X X X X 26 Y Y Y X Y X X X 27 Z Y Y X Y X X X 28Z Y Y X X X Y X 29 Y Y X X Y X X X 30 Y X X X X X X X 31 Y Y X X Y X X X32 Y X Y X X X X X 33 Z Z Z Z Z Z Z Y 34 X X X X X X X X 35 X X X X X XX X 36 Y Y X X X X X X 37 Y Y Y X Y X Y X 38 Z Z Z Z Z Y Z Y 39 X X X XX X X X 40 X X X X X X X X 41 Y X X X X X X X 42 Z Z Y X Y Y Z Z 43 X XX X X X X X 44 Y Y Y X Y X Y X 45 Z Z Y X Y X Y X 46 X X X X X X X X 47X X X X X X X X 48 Z Y Y X Y X Y X 49 X X X X X X X X 50 X X X X X X X X51 Y Y X X X Y Z Y 52 Z Y Y X Y X X X 53 Y Y Y X Y X X X 54 Z Z Z Z Z ZZ Y 55 Y X X X X X X X 56 X X X X X X X X 57 Y X X X X X X X 58 Z Z Z YZ X X X 59 Y Y Y X X X Z Y 60 X X X X X X X X 62 X X X X X X X X 64 Y XX X X X X X Tazobactam Y Y Y X X Z Z Y Clavulanic X X X X X Z Z Z Acid X= MPC_(@4) ≦5 μg/mL Y = 5 μg/mL < MPC_(@4) ≦ 20 μg/mL Z = MPC_(@4) >20μg/mL

Example 66. Potentiation of Tigemonam

Selected β-lactamase inhibitors were also tested for their ability topotentiate the monobactam tigemonam. The potentiation effect wasobserved as the ability of BLI compounds to inhibit growth in thepresence of sub-inhibitory concentration of tigemonam. MICs of teststrains varied from 16 μg/mL to >64 μg/mL. Tigemonam was present in thetest medium at 4 μg/mL. Compounds were tested at concentrations up to 40μg/mL. In this assay potency of compounds was reported as the minimumconcentration of BLI required to inhibit growth of bacteria in thepresence of 4 μg/mL of aztreonam (MPC_(@4)). Table 2 summarizes the BLIpotency of tigemonam potentiation (MPC_(@4)) for various strainsoverexpressing class A (ESBL) and class C beta-lactamases. Tigemonam MICfor each strain is also shown.

TABLE 2 Activity of BLIs to potentiate tigemonam against strainsexpressing class A and class C enzymes. Tigemonam MIC(μg/mL) >64 >64 >64 TIG TIG >64 >64 TIG 16 MPC₄ MPC₄ TIG TIG MPC₄ 32 TIGCTX-M- CTX-M- MPC₄ MPC₄ TEM- TIG MPC4 14 15 SHV-5 SHV-12 10 MPC4 CMY-6Compound KP1005 KP1009 ec308 KP1010 ec302 ECL1002 EC1010 1 X X X X Y X X2 X X X X X X X 3 X X X X Y X X 4 Z Z Z Z Z Y X 5 Z Z Z Y Y X X 6 Y X XX Y X X 7 X X X X Y X X 8 X X X X X X X 9 Z Z Z Y Z X X 10 Z Z Z Z Z Y X11 Z Y Y X Z X X 12 Z Z Z Y Z X X 13 X X X X X X X 14 Z Y Y Y Z X X 15 ZY Y X Y X X 16 Y Y Y X Y X X 17 Z Z Z Y Z Y X 18 Z Z Z X X X X 19 Z Y YX Z X X 20 Y Y Y X Y X X 21 Z Y Z Y Z X X 22 Z Y Y X Y X X 23 Z Y Y X YX X 24 Z X X X X X X 25 Z X X X X X X 26 Z Y Y X Z X X 27 Z Z Z Y Z X X28 Z Z X X Y X X 29 Y Z Y Y Z X X 30 Y Y Y X Y X X 31 Y Y X X Y X X 32 YY Y X Z X X 33 Z Z Z Z Z X X 34 Z X X X X X X 35 Y X X X X X X 36 Y Y YX Z X X 37 Z Z Z Y Z X X 38 Z Z Z Z Z Y X 39 Y X X X Y X X 40 X X X X XX X 41 Y X X X Y X X 42 Z Z Z Y Z Y X 43 X X X X Y X X 44 Z Z Z Y Z X X45 Z Z Z X Z X X 46 Z X X X Y X X 47 X X X X X X X 48 Z Z Z Y Z X X 49 XX X X Y X X 50 X X X X X X X 51 Z Z Y X Y X X 52 Z Z Z X Z X X 53 Z Z ZY Z X X 54 Z Z Z Z Z Y X 55 Z Y X X Y X X 56 X X X X X X X 57 Y Y Y X YX X 58 Z Z Z Z Z X X 59 Z Y Z Y Y Y X 60 X X X X X X X 62 Y Y Y X Y X X64 Y Y Y X X X X Tazobactam Y Y X X X Y X Clavulanic X X X X X Z Z AcidX = MPC_(@4) ≦5 μg/mL Y = 5 μg/mL < MPC_(@4) ≦ 20 μg/mL Z = MPC_(@4) >20μg/mL

Example 67. Potentiation of Biapenem

β-lactamase inhibitors were also tested for their ability to potentiatethe carbapenem biapenem against strains producing class A (KPC) andclass D (OXA-48) carbapenemases. The potentiation effect was observed asthe ability of BLI compounds to inhibit growth in the presence of asub-inhibitory concentration of biapenem. Biapenem MIC of test strainswere 16-32 μg/mL. Biapenem was present in the test medium at 1 μg/mL.Compounds were tested at concentrations up to 40 μg/mL. In this assaypotency of compounds was reported as the minimum concentration of BLIrequired to inhibit growth of bacteria in the presence of 1 μg/mL ofbiapenem (MPC_(@1)). Table 3 summarizes the BLI potency of biapenempotentiation (MPC_(@1)) for two strains overexpressing class A (KPC) andclass D (OXA-48) carbapenemases. Biapenem MIC for each strain is alsoshown.

TABLE 3 Activity of BLIs to potentiate biapenem against strainsexpressing class A (KPC) or class D (OXA-48) carbapenemases. BiapenemMIC (μg/mL) 32 16 BPM MPC₁ BPM MPC₁ KP1004 OXA-48 Compound KPC-2 KP10861 X Y 2 X X 3 X X 4 X Z 5 X X 6 X X 7 X X 8 X X 9 X X 10 X Y 11 X Y 12 XY 13 X X 14 X X 15 X X 16 X Y 17 X X 18 X X 19 X X 20 X X 21 X X 22 X Y23 X X 24 X X 25 X X 26 X X 27 X Y 28 X X 29 X X 30 X Y 31 X X 32 X X 33X X 34 X X 35 X X 36 X X 37 X X 38 X Y 39 X X 40 X X 41 X X 42 X X 43 XX 44 X X 45 X X 46 X Y 47 X X 48 X X 49 X X 50 X X 51 X X 52 X X 53 X X54 X Z 55 X X 56 X X 57 X X 58 X X 59 X X 60 X X 62 X X 64 X YTazobactam Z Y Clavulanic Acid Y Z X = MPC_(@1) ≦ 5 μg/mL Y = 5 μg/mL <MPC_(@1) ≦ 20 μg/mL Z = MPC_(@1) > 20 μg/mL

Example 68. Potentiation of Meropenem

β-lactamase inhibitors were also tested for their ability to potentiatethe carbapenem meropenem against strains of Acinetobacter baumanniiproducing class D (OXA-23 and OXA-72) carbapenemases. The potentiationeffect was observed as the ability of BLI compounds to inhibit growth inthe presence of a sub-inhibitory concentration of meropenem. MeropenemMIC of test strains were 32 to >64 μg/mL. Meropenem was present in thetest medium at 8 μg/mL. Compounds were tested at concentrations up to 20μg/mL. In this assay potency of compounds was reported as the minimumconcentration of BLI required to inhibit growth of bacteria in thepresence of 8 μg/mL of meropenem (MPC_(@8)). Table 4 summarizes the BLIpotency of meropenem potentiation (MPC_(@8)) for two strainsoverexpressing OXA-72 and OXA-23 carbapenemases. Meropenem MIC for eachstrain is also shown.

TABLE 4 Activity of BLIs to potentiate meropenem against strainsexpressing class D carbapenemases from Acinetobacter baumannii MeropenemMIC (μg/mL) >64 32 MPM MPC₈ MPM MPC₈ AB1053 AB1054 Compound OXA-72OXA-23 1 ND ND 2 ND ND 3 Y Z 4 ND ND 5 Z Y 6 X X 7 X X 8 X X 9 Z Z 10 ZZ 11 X Y 12 Y Y 13 X X 14 X X 15 X X 16 X Y 17 X X 18 X X 19 X X 20 Y Y21 X X 22 Z Y 23 X X 24 X X 25 X X 26 X Y 27 Y Y 28 X X 29 X Y 30 X X 31X X 32 X X 33 Y Y 34 X X 35 X X 36 Y X 37 Z Z 38 Z Z 39 X X 40 Z Z 41 XX 42 Z Z 43 X X 44 X Y 45 X X 46 X Y 47 X X 48 X Y 49 Y Y 50 Y Y 51 Z Z52 Z Z 53 X X 54 Z Z 55 Z Z 56 X X 57 X X 58 Z Z 59 Y Z 60 X X 62 X X 64Y Y Tazobactam ND ND Clavulanic Acid ND ND ND = Not determined. X =MPC_(@1) ≦ 5 μg/mL Y = 5 μg/mL < MPC_(@1) ≦ 20 μg/mL Z = MPC_(@1) > 20μg/mL

Example 69. Inhibitory Activity

K_(i) values of inhibition of purified class A, C and D enzymes weredetermined spectrophotometrically using nitrocefin as reportersubstrate. Purified enzymes were mixed with various concentrations ofinhibitors in reaction buffer and incubated for 10 min at roomtemperature. Nitrocefin was added and substrate cleavage profiles wererecorded at 490 nm every 10 sec for 10 min. The results of theseexperiments are presented in Table 5. These experiments confirmed thatthe described compounds are inhibitors with a broad-spectrum of activitytowards various β-lactamases.

TABLE 5 Activity of BLIs (Ki, uM) to inhibit cleavage of nitrocefin bypurified class A, C and D enzymes Ki Ki Ki Ki Ki Ki (CTX- (SHV- (TEM-(KPC- Ki Ki (Pa- (OXA- (OXA- M-14, 12, 10, 2, (P99, AmpC, 48, 23, NCF),NCF), NCF), NCF), NCF), NCF), NCF), NCF), Compound uM uM uM uM uM uM uMuM 1 X X X X X ND X ND 2 X X X X X ND X ND 3 X X X X X X X X 4 X X X X XND X ND 5 X X X X X ND X Y 6 X X X X X X X X 7 X X X X X X X X 8 X ND XX X X X X 9 X Y Y X X X X Y 10 X Y Y X Y X X Z 11 X ND X X X X X X 12 XND X X X Y X Y 13 X ND X X X X X X 14 X ND X X Y Z X X 15 X X X X X X XX 16 X ND X X X X X X 17 X Y Y X Y Y X X 18 X X X X X X X X 19 X ND X XX X X X 20 X ND X X X X X X 21 X ND X X X X X X 22 X ND X X X X X X 23 XX X X X X X X 24 X X X X X X X X 25 X X X X X X X X 26 ND ND X X X X X X27 X ND X X X Y X X 28 X ND X X X X X X 29 X ND X X X X X X 30 ND ND X XX X X X 31 ND ND X X X X X X 32 ND ND X X X X X X 33 X ND Z Z Y Z X X 34X ND X X X X X X 35 X ND X X X X X X 36 ND ND X X X X X X 37 ND ND X X XX X X 38 ND ND Y Y Z Z X Z 39 X ND X X X X X X 40 ND ND X X X X X ND 41X ND X X X X X X 42 X ND X X Y Y X Y 43 X ND X X X X X X 44 ND ND X X XX X X 45 X ND X X X X X X 46 X ND X X X X X X 47 ND ND X X X X X X 48 XND X X Y Y X X 49 X ND X X X X X X 50 X ND X X X X X X 51 X ND X X X X XX 52 X ND X X X X X Y 53 X ND X X X X X X 54 ND ND Z Z Y Z X Y 55 X ND XX X X X X 56 X X X X X X X X 57 X ND X X X X X X 58 X ND Y X X X X Y 59X ND X X Z Y X Z 60 X ND X X X X X X 62 X ND X X X X X X 64 X ND X X X XX X Tazobactam X X X Z Z Y Y ND Clavulanic X X X Z Z ND Z ND Acid X =K_(i) ≦0.1 μM Y = 0.1 μM < K_(i) ≦ 1 μM Z = K_(i) >1 μM ND = notdetermined

Example 70 MexAB-OprM Dependent Efflux of BLIs

Efflux of BLIs from Pseudomonas aeruginosa by the MexAB-OprM efflux pumpwas also evaluated. The plasmid expressing the gene encoding KPC-2 wasintroduced into two strains of P. aeruginosa, PAM1032 and PAM1154 thatoverexpressed or lacked MexAB-OprM, respectively. Due to expression ofKPC-2 both strains became resistant to biapenem. Biapenem is notaffected by efflux in P. aeruginosa and both strains had the samebiapenem MIC of 32 μg/ml. Potency of BLIs to potentiate biapenem inthese strains was determined. Potency was defined as the ability of BLIto decrease MIC of biapenem 64-fold, from 32 μg/ml to 0.5 μg/ml, orMPC₆₄. The ratio of MPC₆₄ values for each BLI in PAM1032/KPC-2 (effluxproficient) and PAM1154/KPC-2 (efflux deficient) was determined togenerate the Efflux Index (EI).

TABLE 6 MexAB-OprM Dependent Efflux of BLIs from P. aeruginosa PAM1032/PAM1154/ KPC-2 KPC-2 Biapenem Biapenem Compound MPC64 MPC64 EI 1 40 2.516 2 20 1.25 16 3 20 2.5 8 4 >80 5 >16 5 20 0.3 64 6 5 0.3 16 7 2.5 0.64 8 5 0.6 8

Although the invention has been described with reference to embodimentsand examples, it should be understood that numerous and variousmodifications can be made without departing from the spirit of theinvention. Accordingly, the invention is limited only by the followingclaims.

What is claimed is:
 1. A compound having the structure of the formulaIII′ or IV′:

or a pharmaceutically acceptable salt thereof, wherein: A is a C₆₋₁₀aryl or 5-10 membered heteroaryl; m is 0, 1 or 2; Y⁷ is selected fromthe group consisting of —CH₂—, —O—, —S— and —NR¹—; n¹ is 1, 2 or 3; Q¹and Q² are H; each R⁷ is independently selected from the groupconsisting of OH, optionally substituted —O—C₁₋₆ alkyl, —NR¹R², and—N(OR¹)R²; and Y⁴ is selected from the group consisting of —O—, —S—, and—NR¹—; Y⁵ is selected from the group consisting of —OH, —SH, and —NHR¹;Y⁶ is selected from the group consisting of —OH, optionally substituted—O—C₁₋₆ alkyl, —NR¹R², and —N(OR¹)R²; each R¹, R², R³ and R⁴ areindependently selected from —H, halogen, optionally substitutedC₁₋₄alkyl, optionally substituted O—C₁₋₄alkyl, optionally substitutedC₃₋₇ carbocyclyl, optionally substituted 4-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl; R⁵ is present 1 to 5 times and each R⁵ isindependently selected from the group consisting of H, OH, halogen,—C(O)OR¹; —C(O)NR¹R²; —C(O)NR¹OR²; —C(═NR¹)R²; —C(═NR¹)NR²R³;—NR¹C(O)R²; —NR¹C(O)NR²R³; —NR¹C(O)OR²; —NR¹S(O)₂R²; —NR¹S(O)₂NR²R³;—NR¹CR²(═NR³); —NR¹C(═NR²)NR³R⁴; —S(O)(CH₂)₁₋₃R⁴, —S(O)₂NR¹R²,—S(O)₂NR¹OR³, —NR¹S(O)₂NR¹OR³, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₇ carbocyclyl, optionallysubstituted 5-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, cyano, C₁-C₆alkoxy(C₁-C₆)alkyl, aryloxy, sulfhydryl (mercapto), and—(CH₂)_(p)—Y³—(CH₂)_(q)M′; p and q are each independently 0, 1, or 2; Y³is selected from the group consisting of —S—, —S(O)—, —S(O)₂—, —O—,—CR¹R²—, and —NR¹—; M′ is selected from the group consisting of halogen,cyano, —OH, —C(O)NR¹R²; —C(O)NR¹OR²; —NR¹C(O)R²; —NR¹C(O)NR²R³;—NR¹C(O)OR²; —NR¹S(O)₂R²; —NR¹S(O)₂NR²R³; —C(═NR¹)R²; —C(═NR¹)NR²R³;—NR¹CR²(═NR³); —NR¹C(═NR²)NR³R⁴; —S(O)₂R¹, —S(O)₂NR¹R², —S(O)₂NR¹OR³,C₁₋₄ alkyl optionally substituted with 0-2 substituents selected fromthe group consisting of —OR¹, —CN, —NR¹R², -heterocyclyl, halogen,—C(O)NR¹R², and —NR¹C(O)R²; C₂₋₄ alkenyl optionally substituted with 0-2substituents selected from the group consisting of C₁₋₄ alkyl,—(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl,halogen, —C(O)NR¹R², and —NR¹C(O)R²; C₂₋₄ alkynyl optionally substitutedwith 0-2 substituents selected from the group consisting of C₁₋₄ alkyl,—(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl,halogen, —C(O)NR¹R², and —NR¹C(O)R²; C₆₋₁₀ aryl optionally substitutedwith 0-2 substituents selected from the group consisting of C₁₋₄ alkyl,—(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl,halogen, —C(O)NR¹R², and —NR¹C(O)R²; C₃₋₇ carbocyclyl optionallysubstituted with 0-2 substituents selected from the group consisting ofC₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,—(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and —NR¹C(O)R²; 5-10membered heteroaryl optionally substituted with 0-2 substituentsselected from the group consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR,—(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen,—C(O)NR¹R², and —NR¹C(O)R²; and 3-10 membered heterocyclyl optionallysubstituted with 0-2 substituents selected from the group consisting ofC₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,—(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and —NR¹C(O)R²; R⁶ isselected from the group consisting of H, halogen, substituted —C₁₋₆alkyl, —OH, —C(O)OR, —P(O)(OR)₂, P(O)(OR)R¹ optionally substituted—O—C₁₋₆ alkyl, —NR¹R², —N(OR¹)R², optionally substituted —S—C₁₋₆ alkyl,—C(O)NR¹R², —S(O)₂NR¹R², CN, optionally substituted —S(O)—C₁₋₆ alkyl,optionally substituted —S(O)₂—C₁₋₆ alkyl, and a carboxylic acidisostere; R is selected from —H, alkali metal, NH₄ ⁺, —C₁₋₉alkyl,—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl,—CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl, —CR¹⁰R¹¹OC(O)NR¹⁰C₁₋₉-alkyl,—CR¹⁰R¹¹OC(O)NR¹⁰C₆₋₁₀aryl, and

R¹⁰ and R¹¹ are independently selected from the group consisting of —H,optionally substituted C₁₋₄alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 5-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl.
 2. The compound of claim 1, having the structure ofthe formula Ill or IV:

or a pharmaceutically acceptable salt thereof, wherein: Y⁷ is selectedfrom the group consisting of CH₂, O, S and NH; each R¹, R², R³ and R⁴are independently selected from —H, optionally substituted C₁₋₄alkyl,optionally substituted C₃₋₇ carbocyclyl, optionally substituted 4-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, and optionallysubstituted 5-10 membered heteroaryl; R⁵ is present 1 to 5 times andeach R⁵ is independently selected from the group consisting of H, OH,halogen, —CF₃, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ alkynyl, optionally substituted C₁-C₆ heteroalkyl,optionally substituted C₃-C₇ carbocyclyl, optionally substituted 5-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, optionallysubstituted 5-10 membered heteroaryl, cyano, C₁-C₆ alkoxy(C₁-C₆)alkyl,aryloxy, sulfhydryl (mercapto), and —(CH₂)_(p)—Y³—(CH₂)_(q)M′; p and qare each independently 0 or 1; Y³ is selected from the group consistingof —S—, —S(O)—, —S(O)₂—, —O—, —CH₂—, and —NR¹—; M′ is selected from thegroup consisting of —C(O)NR¹R²; —C(O)NR¹OR²; —NR¹C(O)R²; —NR¹C(O)NR²R³;—NR¹C(O)OR²; —NR¹S(O)₂R²; —NR¹S(O)₂NR²R³; —C(═NR)R²; —C(═NR¹)NR²R³;—NR¹CR²(═NR³); —NR¹C(═NR²)NR³R⁴; C₁₋₄ alkyl optionally substituted with0-2 substituents selected from the group consisting, —OR¹, —NR¹R²,halogen, —C(O)NR¹R², and —NR¹C(O)R²; C₆₋₁₀ aryl optionally substitutedwith 0-2 substituents selected from the group consisting of C₁₋₄ alkyl,—OR¹, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R²; C₃₋₇ carbocyclyloptionally substituted with 0-2 substituents selected from the groupconsisting of C₁₋₄ alkyl, —OR¹, —NR¹R², halogen, —C(O)NR¹R², and—NR¹C(O)R²; 5-10 membered heteroaryl optionally substituted with 0-2substituents selected from the group consisting of C₁₋₄ alkyl, —OR¹,—NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R²; and 3-10 memberedheterocyclyl optionally substituted with 0-2 substituents selected fromthe group consisting of C₁₋₄ alkyl, —OR¹, —NR¹R², halogen, —C(O)NR¹R²,and —NR¹C(O)R²; R⁶ is selected from the group consisting of H, halogen,substituted —C₁₋₆ alkyl, —OH, —C(O)OR, optionally substituted —O—C₁₋₆alkyl, —NR¹R², —N(OR¹)R², optionally substituted —S—C₁₋₆ alkyl,—C(O)NR¹R², —S(O)₂NR¹R², CN, optionally substituted —S(O)—C₁₋₆ alkyl,optionally substituted —S(O)₂—C₁₋₆ alkyl, and a carboxylic acidisostere; and R is selected from —H, alkali metal, NH₄ ⁺, —C₁₋₉alkyl,—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl,—CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl and


3. The compound of claim 1 or 2, having the structure of Formula (IIIa)

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1 or 2, having the structure of Formula (IIIb)

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1 or 2, having the structure of Formula (IIIc)

or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, or 2;and J, L, and M are each independently selected from the groupconsisting of CR⁵ and N.
 6. The compound of claim 1, 2, or 5, having thestructure of Formula (IIId)

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1 or 2, having the structure of Formula (IVa)

or a pharmaceutically acceptable salt thereof wherein: m is 0, 1, or 2;and J, L, and M are each independently selected from the groupconsisting of CR⁵ and N.
 8. The compound of claim 1, 2, or 7, having thestructure of Formula (IVb)

or a pharmaceutically acceptable salt thereof.
 9. The compound of anyone of claims 1 to 8, wherein Y⁷ is CH₂, O, or S.
 10. The compound ofclaim 1 or 2, having the structure of (III-1) or (IV-1):

or a pharmaceutically acceptable salt thereof, wherein: J, L, and M areeach independently selected from the group consisting of CR⁵ and N. 11.The compound of claim 10, having the structure of (III-2) or (IV-2):

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1, wherein n¹ is 1 and Q¹ and Q² are deuterium.
 13. The compound of anyone of claims 1-2, 4-5, 7, and 12, wherein Y⁷ is O, n¹ is 1, and m is 1.14. The compound of any one of claims 10 to 13, wherein M is CR⁵. 15.The compound of any one of claims 10 to 13, wherein M is N.
 16. Thecompound of any one of claims 10 to 15, wherein J and L are eachindependently CR⁵.
 17. The compound of claim 16, wherein J and L are CH.18. The compound of any one of claims 10 to 13, wherein J is N.
 19. Thecompound of any one of claims 10 to 15 and 18, wherein L and M are eachindependently CR⁵.
 20. The compound of claim 19, wherein L and M are CH.21. The compound of any one of claims 10 to 13, wherein L is N.
 22. Thecompound of any one of claims 10 to 13 and 21, wherein J and M are eachindependently CR⁵.
 23. The compound of claim 22, wherein J and M are CH.24. The compound of any one of claims 10 to 15 and 21, wherein M is CH.25. The compound of any one of claims 1 to 24, wherein each R⁵ isindependently selected from the group consisting of C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₇ carbocyclyl, C₁-C₆ heteroalkyl, 5-10membered heterocyclyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, cyano,hydroxy, —OR³, —SR³, —S(O)₂M′, —P(O)R¹M′, and halogen.
 26. The compoundof claim 25, wherein R⁵ is halogen.
 27. The compound of claim 26,wherein R⁵ is F.
 28. The compound of claim 25, wherein R⁵ is alkoxy. 29.The compound of claim 28, wherein R⁵ is —OCH₃.
 30. The compound of claim28, wherein R⁵ is —OCH₂CH₃.
 31. The compound of any one of claims 1 to25, wherein R⁵ is —OH.
 32. The compound of any one of claims 1 to 25,wherein R⁵ is —SH.
 33. The compound of any one of claims 1 to 25,wherein R⁵ is —SCH₃.
 34. The compound of any one of claims 1 to 25,wherein R⁵ is —S(O)₂M′.
 35. The compound of claim 34, wherein R⁵ is—S(O)₂CH₃.
 36. The compound of any one of claims 1 to 25, wherein R⁵ is—SOM′.
 37. The compound of claim 36, wherein R⁵ is —SOCH₃.
 38. Thecompound of any one of claims 1 to 25, wherein R⁵ is cyano.
 39. Thecompound of any one of claims 1 to 25, wherein R⁵ is —C≡CH.
 40. Thecompound of any one of claims 1 to 24, wherein R⁵ is —CHF₂.
 41. Thecompound of any one of claims 1 to 24, wherein R⁵ is —CF₃.
 42. Thecompound of any one of claims 1 to 24, wherein R⁵ is —C(O)NR¹R².
 43. Thecompound of claim 42, wherein R⁵ is —C(O)NH₂.
 44. The compound of anyone of claims 1 to 24, wherein R⁵ is —C(═NR)R².
 45. The compound ofclaim 44, wherein R⁵ is —CH═N—OCH₃.
 46. The compound of any one ofclaims 1 to 24, wherein R⁵ is —COOR¹.
 47. The compound of claim 46,wherein R⁵ is —COOH.
 48. The compound of any one of claims 1 to 24,wherein R⁵ is a C₂₋₄ alkynyl, triazole, or diazole, optionallysubstituted with 0-2 substituents selected from —(CH₂)₀₋₄OR¹,—(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen,—C(O)NR¹R², and —NR¹C(O)R².
 49. The compound of claim 48, wherein R⁵ is


50. The compound of any one of claims 1 to 24, wherein R⁵ is—(CH₂)_(p)—Y³—(CH₂)_(q)M′.
 51. The compound of claim 50, wherein Y³ is—S—, —O—, or —NH—.
 52. The compound of claim 50 or 51, wherein M′ is a5-10 membered heteroaryl or 3-10 membered heterocyclyl, each optionallysubstituted with 0-2 substituents selected from the group consisting ofC₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,—(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and —NR¹C(O)R².
 53. Thecompound of claim 52, wherein M′ is azetine, thiadiazole, triazole,dioxolane, pyridine, morpholine, or cyclopropyl, each optionallysubstituted with 0-2 substituents selected from the group consisting ofC₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,—(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and —NR¹C(O)R².
 54. Thecompound of claim 53, wherein M′ is

each optionally substituted with 0-2 substituents selected from thegroup consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN,—(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and—NR¹C(O)R².
 55. The compound of claim 54, wherein M′ is


56. The compound of claim 50 or 51, wherein M′ is cyano.
 57. Thecompound of claim 50 or 51, wherein M′ is —OH.
 58. The compound of claim50 or 51, wherein M′ is —S(O)₂R or —S(O)₂NR¹R².
 59. The compound ofclaim 58, wherein M′ is —S(O)₂CH₃ or —S(O)₂NH₂.
 60. The compound ofclaim 50 or 51, wherein M′ is —C(O)NR¹R².
 61. The compound of claim 60,wherein M′ is —C(O)NH₂.
 62. The compound of claim 50, wherein Y³ is—S(O)— or —S(O)₂—.
 63. The compound of any one of claims 50-51 and 62,wherein M′ is C₁₋₄ alkyl optionally substituted with 0-2 substituentsselected from the group consisting of —OR¹, —CN, —NR¹R², -heterocyclyl,halogen, —C(O)NR¹R², and —NR¹C(O)R²; C₂₋₄ alkenyl optionally substitutedwith 0-2 substituents selected from the group consisting of C₁₋₄ alkyl,—(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl,halogen, —C(O)NR¹R², and —NR¹C(O)R²; or C₂₋₄ alkynyl optionallysubstituted with 0-2 substituents selected from the group consisting ofC₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,—(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and —NR¹C(O)R².
 64. Thecompound of claim 63, wherein M′ is —C≡CH.
 65. The compound of claim 63,wherein M′ is —C≡C—(CH₂)₀₋₄OR¹, —C≡C—(CH₂)₀₋₄NR¹R², or—C≡C—(CH₂)₀₋₄-heterocyclyl.
 66. The compound of claim 65, wherein M′ is—C≡C—(CH₂)—OCH₃, —C≡C—(CH₂)—OH, —C≡C—(CH₂)—NH₂, or


67. The compound of claim 63, wherein M′ is —(CH₂)₃NH₂, CH₂F, CHF₂, CF₃,CH(CH₂OH)₂, or CH₂N(CH₃)₂.
 68. The compound of claim 63, wherein M′ isC₁₋₄ alkyl.
 69. The compound of any one of claims 10 to 12, wherein R⁵is present twice.
 70. The compound of any one of claims 10 to 12,wherein: L and M are each independently CR⁵; J is CH; and each R⁵ isindependently selected from the group consisting of OH, halogen, CN,—C(O)OR¹; —C(O)NR¹R²; —C(O)NR¹OR²; —NR¹C(O)R²; —NR¹C(O)NR²R³;—NR¹C(O)OR²; —NR¹S(O)₂R²; —NR¹S(O)₂NR²R³; —C(═NR¹)R²; —C(═NR¹)NR²R³;—NR¹CR²(═NR³); —NR¹C(═NR²)NR³R⁴; —S(O)(CH₂)₁₋₃R⁴, —S(O)₂NR¹R²,—S(O)₂NR¹OR³, —NR¹S(O)₂NR¹OR³, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₁-C₆heteroalkyl, optionally substituted C₃-C₇ carbocyclyl, optionallysubstituted 5-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, cyano, C₁-C₆alkoxy(C₁-C₆)alkyl, aryloxy, sulfhydryl (mercapto), and—(CH₂)_(p)—Y³—(CH₂)_(q)M′.
 71. The compound of any one of claims 69 to70, wherein each R⁵ is independently halogen or —OM′
 72. The compound ofclaim 71, wherein each R⁵ is independently F or —OCH₃.
 73. The compoundof claim 71, wherein each R⁵ is independently Cl or —OCH₃.
 74. Thecompound of any one of claims 1 to 73, wherein R⁶ is —COOR or—P(O)(OR)₂.
 75. The compound of claim 74, wherein R⁶ is —COOH or—P(O)(OH)₂.
 76. The compound of claim 1, having the structure selectedfrom the group consisting of

and pharmaceutically acceptable salts thereof.
 77. The compound of claim1, having the structure selected from the group consisting

and pharmaceutically acceptable salts thereof.
 78. A compound having thestructure selected from the group consisting of

and pharmaceutically acceptable salts thereof.
 79. A compound having thestructure of the formula I′ or II′:

or a pharmaceutically acceptable salt thereof, wherein: each G isindependently selected from the group consisting of —C(O)R⁴,—C(O)(CH₂)₀₋₃SR³, —C(O)(CH₂)₁₋₃R⁴, —C(O)OR³, —C(O)NR¹R², —C(O)NR¹OR³,—NR¹C(O)R⁴, —NR¹C(O)NR¹R², —NR¹C(O)OR³, —NR¹S(O)₂R³, —NR¹S(O)₂NR¹R²,—C(═NR¹)R⁴, —C(═NR¹)NR¹R², —NR¹CR⁴(═NR²), —NR¹C(═NR²)NR¹R², —S(O)₂R³,—S(O)(CH₂)₁₋₃R³, —S(O)₂NR¹R², —S(O)₂NR¹OR³, —NR¹S(O)₂NR¹OR³, —CN, —OR¹,—SR¹, —NR¹R², optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀alkenyl, optionally substituted C₂₋₁₀alkynyl, optionallysubstituted C₃₋₇ carbocyclyl, optionally substituted 5-10 memberedheterocyclyl, optionally substituted C₆₋₁₀aryl, optionally substituted5-10 membered heteroaryl, optionally substitutedC₃₋₇carbocyclyl-C₁₋₆alkyl, optionally substituted 5-10 memberedheterocyclyl-C₁₋₆alkyl, optionally substituted C₆₋₁₀aryl-C₁₋₆alkyl, andoptionally substituted 5-10 membered heteroaryl-C₁₋₆alkyl; Y¹ isselected from the group consisting of CR¹ and N; each Y² isindependently selected from the group consisting of —S—, —S(O)—,—S(O)₂—, —O—, —CR¹R²—, and —NR²—, or Y²—(CH₂)_(n)-G is CH₃; Y⁴ isselected from the group consisting of —O—, —S—, and —NR¹—; Y⁵ isselected from the group consisting of —OH, —SH, and —NHR¹; Y⁶ isselected from the group consisting of —OH, optionally substituted—O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R², Q¹ and Q² is each independently Hor —Y²—(CH₂)_(n)-G; each n is independently an integer from 0 to 3; m is0 or 1; A is selected from the group consisting of C₃₋₁₀ carbocyclyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl;each R¹, R², R³, and R⁴ are independently selected from —H, halogen,optionally substituted C₁₋₄alkyl, optionally substituted O—C₁₋₄alkyl,optionally substituted C₃₋₇ carbocyclyl, optionally substituted 4-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, and optionallysubstituted 5-10 membered heteroaryl; R⁵ is present 1 to 5 times andeach R⁵ is independently selected from the group consisting of H, OH,halogen, CN, —C(O)OR¹; —C(O)NR¹R²; —C(O)NR¹OR²; —NR¹C(O)R²;—NR¹C(O)NR²R³; —NR¹C(O)OR²; —NR¹S(O)₂R²; —NR¹S(O)₂NR²R³; —C(═NR¹)R²;—C(═NR¹)NR²R³; —NR¹CR²(═NR¹); —NR¹C(═NR²)NR³R⁴; —S(O)(CH₂)₁₋₃R⁴,—S(O)₂NR¹R², —S(O)₂NR¹OR³, —NR¹S(O)₂NR¹OR³, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₁-C₆ heteroalkyl, optionally substituted C₃-C₇ carbocyclyl, optionallysubstituted 5-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, cyano, C₁-C₆alkoxy(C₁-C₆)alkyl, aryloxy, sulfhydryl (mercapto), and—(CH₂)_(p)—Y³—(CH₂)_(q)M′; p and q are each independently 0, 1, or 2; Y³is selected from the group consisting of —S—, —S(O)—, —S(O)₂—, —O—,—CR¹R²—, and —NR¹—; M′ is selected from the group consisting of halogen,cycano, —OH, —C(O)NR¹R²; —C(O)NR¹OR²; —NR¹C(O)R²; —NR¹C(O)NR²R³;—NR¹C(O)OR²; —NR¹S(O)₂R²; —NR¹S(O)₂NR²R³; —C(═NR¹)R²; —C(═NR¹)NR²R³;—NR¹CR²(═NR³); —NR¹C(═NR²)NR³R⁴; —S(O)₂R¹, —S(O)₂NR¹R², —S(O)₂NR¹OR³,C₁₋₄ alkyl optionally substituted with 0-2 substituents selected fromthe group consisting of —OR¹, —CN, —NR¹R², -heterocyclyl, halogen,—C(O)NR¹R², and —NR¹C(O)R²; C₂₋₄ alkenyl optionally substituted with 0-2substituents selected from the group consisting of C₁₋₄ alkyl,—(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl,halogen, —C(O)NR¹R², and —NR¹C(O)R²; C₂₋₄ alkynyl optionally substitutedwith 0-2 substituents selected from the group consisting of C₁₋₄ alkyl,—(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl,halogen, —C(O)NR¹R², and —NR¹C(O)R²; C₆₋₁₀ aryl optionally substitutedwith 0-2 substituents selected from the group consisting of C₁₋₄ alkyl,—(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl,halogen, —C(O)NR¹R², and —NR¹C(O)R²; C₃₋₇ carbocyclyl optionallysubstituted with 0-2 substituents selected from the group consisting ofC₁₋₄ alkyl, —(CH₂)₀₋₄OR¹, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,—(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and —NR¹C(O)R²; 5-10membered heteroaryl optionally substituted with 0-2 substituentsselected from the group consisting of C₁₋₄ alkyl, —(CH₂)₀₋₄OR¹,—(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R², —(CH₂)₀₋₄-heterocyclyl, halogen,—C(O)NR¹R², and —NR¹C(O)R²; and 3-10 membered heterocyclyl optionallysubstituted with 0-2 substituents selected from the group consisting ofC₁₋₄ alkyl, —(CH₂)₀₋₄OR, —(CH₂)₀₋₄CN, —(CH₂)₀₋₄NR¹R²,—(CH₂)₀₋₄-heterocyclyl, halogen, —C(O)NR¹R², and —NR¹C(O)R²; R⁶ isselected from the group consisting of is selected from the groupconsisting of —H, halogen, optionally substituted —C₁₋₆ alkyl, —OH,—C(O)OR, —P(O)(OR)₂, P(O)(OR)R¹, optionally substituted —O—C₁₋₆ alkyl,—NR¹R², —N(OR³)R², optionally substituted —S—C₁₋₆ alkyl, —C(O)NR¹R²,—S(O)₂NR¹R², CN, optionally substituted —S(O)—C₁₋₆ alkyl, optionallysubstituted —S(O)₂—C₁₋₆ alkyl, and a carboxylic acid isostere; R isselected from —H, —C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₁₋₉alkyl,—CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl,—CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl, —CR¹⁰R¹¹OC(O)NR¹⁰C₁₋₉alkyl,—CR¹⁰R¹¹OC(O)NR¹⁰C₆₋₁₀aryl, and

R⁷ is selected from the group consisting of OH, optionally substituted—O—C₁₋₆ alkyl, —NR¹R², and —N(OR³)R²; and R¹⁰ and R¹¹ are independentlyselected from the group consisting of —H, optionally substitutedC₁₋₄alkyl, optionally substituted C₃₋₇ carbocyclyl, optionallysubstituted 5-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, and optionally substituted 5-10 membered heteroaryl.
 80. Thecompound of claim 79 having the structure of formula I or II:

each G is independently selected from the group consisting of —C(O)R⁴,—C(O)(CH₂)₀₋₃SR³, —C(O)(CH₂)₁₋₃R⁴, —C(O)OR³, —C(O)NR¹R², —C(O)NR¹OR³,—NR¹C(O)R⁴, —NR¹C(O)NR¹R², —NR¹C(O)OR³, —NR¹S(O)₂R³, —NR¹S(O)₂NR¹R²,—C(═NR¹)R⁴, —C(═NR¹)NR¹R², —NR¹CR⁴(═NR²), —NR¹C(═NR²)NR¹R², —S(O)₂R³,optionally substituted C₁₋₁₀ alkyl, optionally substituted C₂₋₁₀alkenyl,optionally substituted C₂₋₁₀alkynyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 5-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, optionally substituted 5-10 memberedheteroaryl, optionally substituted C₃₋₇carbocyclyl-C₁₋₆alkyl, optionallysubstituted 5-10 membered heterocyclyl-C₁₋₆alkyl, optionally substitutedC₆₋₁₀aryl-C₁₋₆alkyl, and optionally substituted 5-10 memberedheteroaryl-C₁₋₆alkyl; Q is H or —Y²—(CH₂)_(n)-G; each R¹, R², R³, and R⁴are independently selected from —H, optionally substituted C₁₋₄alkyl,optionally substituted C₃₋₇ carbocyclyl, optionally substituted 4-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, and optionallysubstituted 5-10 membered heteroaryl; R⁵ is present 1 to 5 times andeach R⁵ is independently selected from the group consisting of H, OH,halogen, —CF₃, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ alkynyl, optionally substituted C₁-C₆ heteroalkyl,optionally substituted C₃-C₇ carbocyclyl, optionally substituted 5-10membered heterocyclyl, optionally substituted C₆₋₁₀aryl, optionallysubstituted 5-10 membered heteroaryl, cyano, C₁-C₆ alkoxy(C₁-C₆)alkyl,aryloxy, sulfhydryl (mercapto), and —(CH₂)_(p)—Y³—(CH₂)_(q)M′; p and qare each independently 0 or 1; Y³ is selected from the group consistingof —S—, —S(O)—, —S(O)₂—, —O—, —CH₂—, and —NR¹—; M′ is selected from thegroup consisting of —C(O)NR¹R²; —C(O)NR¹OR²; —NR¹C(O)R²; —NR¹C(O)NR²R³;—NR¹C(O)OR²; —NR¹S(O)₂R²; —NR¹S(O)₂NR²R³; —C(═NR¹)R²; —C(═NR¹)NR²R³;—NR¹CR²(═NR³); —NR¹C(═NR²)NR³R⁴; C₁₋₄ alkyl optionally substituted with0-2 substituents selected from the group consisting, —OR¹, —NR¹R²,halogen, C(O)NR¹R², and —NR¹C(O)R²; C₆₋₁₀ aryl optionally substitutedwith 0-2 substituents selected from the group consisting of C₁₋₄ alkyl,—OR¹, —NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R²; C₃₋₇ carbocyclyloptionally substituted with 0-2 substituents selected from the groupconsisting of C₁₋₄ alkyl, —OR¹, —NR¹R², halogen, —C(O)NR¹R², and—NR¹C(O)R²; 5-10 membered heteroaryl optionally substituted with 0-2substituents selected from the group consisting of C₁₋₄ alkyl, —OR¹,—NR¹R², halogen, —C(O)NR¹R², and —NR¹C(O)R²; and 3-10 memberedheterocyclyl optionally substituted with 0-2 substituents selected fromthe group consisting of C₁₋₄ alkyl, —OR¹, —NR¹R², halogen, —C(O)NR¹R²,and —NR¹C(O)R²; and R is selected from —H, —C₁₋₉alkyl,—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, —CR¹⁰R¹¹OC(O)C₆₋₁₀aryl,—CR¹⁰R¹¹OC(O)OC₆₋₁₀aryl and


81. The compound of claim 79 or 80, wherein the compound has thestructure of formula I

or a pharmaceutically acceptable salt thereof.
 82. The compound of anyone of claims 79 to 81, wherein Q is —Y²—(CH₂)_(n)-G.
 83. The compoundof any one of claims 79 to 81, wherein the compound has the structure offormula I-1

or a pharmaceutically acceptable salt thereof, wherein: G is selectedfrom the group consisting of —C(O)R⁴, —C(O)(CH₂)₀₋₃SR³, —C(O)OR³,—C(O)NR¹R², —C(O)NR¹OR³, —NR¹C(O)R⁴, —NR¹C(O)NR¹R², —NR¹C(O)OR³,—NR¹S(O)₂R³, —NR¹S(O)₂NR¹R², —C(═NR¹)R⁴, —C(═NR¹)NR¹R², —NR¹CR⁴(═NR²),—NR¹C(═NR²)NR¹R², —S(O)₂R³, optionally substituted C₁₋₁₀ alkyl,optionally substituted C₂₋₁₀alkenyl, optionally substitutedC₂₋₁₀alkynyl, optionally substituted C₃₋₇ carbocyclyl, optionallysubstituted 5-10 membered heterocyclyl, optionally substitutedC₆₋₁₀aryl, optionally substituted 5-10 membered heteroaryl, optionallysubstituted C₃₋₇carbocyclyl-C₁₋₆alkyl, optionally substituted 5-10membered heterocyclyl-C₁₋₆alkyl, optionally substitutedC₆₋₁₀aryl-C₁₋₆alkyl, and optionally substituted 5-10 memberedheteroaryl-C₁₋₆alkyl; each R¹, R², R³, and R⁴ are independently selectedfrom —H, optionally substituted C₁₋₄alkyl, optionally substituted C₃₋₇carbocyclyl, optionally substituted 5-10 membered heterocyclyl,optionally substituted C₆₋₁₀aryl, and optionally substituted 5-10membered heteroaryl; and R is selected from —H, —C₁₋₉alkyl,—CR¹⁰R¹¹OC(O)C₁₋₉alkyl, —CR¹⁰R¹¹OC(O)OC₁₋₉alkyl, and


84. The compound of any one of claims 79-81 and 83, having the structureof formula Ia:

or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; andJ, L, and M are each independently selected from the group consisting ofCR³ and N.
 85. The compound of any one of claims 79-81 and 83, havingthe structure of (Ib):

or pharmaceutically acceptable salt thereof.
 86. The compound of any oneof claims 79-81 and 83, having the structure of (Ic):

or pharmaceutically acceptable salt thereof.
 87. The compound of claim79 or 80 having the structure of formula IIa:

or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; andJ, L, and M are each independently selected from the group consisting ofCR⁵ and N.
 88. The compound of claim 87, having the structure of (IIb):

or pharmaceutically acceptable salt thereof.
 89. The compound of claim87, having the structure of (IIc):

or pharmaceutically acceptable salt thereof.
 90. The compound of any oneof claims 79-89, wherein Y² is selected from the group consisting of—S—, —SO₂—, —O—, or —NH—.
 91. The compound of any one of claims 79-90,wherein M is N.
 92. The compound of any one of claims 79-90, wherein Mis CR⁵.
 93. The compound of any one of claims 79-92, wherein J and L areeach independently CR⁵.
 94. The compound of any one of claims 79-83,wherein Y⁴ is —O—.
 95. The compound of any one of claims 79-83 whereinR⁷ is —OH.
 96. The compound of any one of claims 79-81 and 83, havingthe structure of Formula (Id):

or pharmaceutically acceptable salt thereof.
 97. The compound of any oneof claims 79-90, wherein: Y² is —O— or —S—; G is selected from the groupconsisting of C₁₋₄alkyl, phenyl, imidazole, pyrazole, triazole,tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole,isothiazole, pyridine, pyrazine, pyrimidine, pyridazine, and pyrazine,each optionally substituted by 0-2 substituents selected from the groupconsisting of hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxy(C₁-C₆)alkyl, aryloxy,halo(C₁-C₆)alkoxy, amino, C-amido, and N-amido; and J, L and M are CR⁵.98. The compound of claim 97, wherein G is C₁₋₄alkyl.
 99. The compoundof claim 98, wherein G is —CH₃.
 100. The compound of claim 97, wherein Gis thiadiazole optionally substituted with amino.
 101. The compound ofclaim 18, wherein G is


102. The compound of any one of claims 79-90, wherein: M is CR⁵; andeach R⁵ is independently selected from the group consisting of —H,—C₁₋₄alkyl, and halogen, —CF₃, and —(CH₂)_(p)—Y³—(CH₂)_(q)M′.
 103. Thecompound of claim 102, wherein R⁵ is halogen.
 104. The compound of claim103, wherein R⁵ is F.
 105. The compound of any one of claims 79-90,wherein: R⁵ is —(CH₂)_(p)—Y³—(CH₂)_(q)M′; m is 0; p is 0; Y³ is S or O;and M′ is hydrogen; hydroxyl; C₁-C₄ alkyl optionally substituted withone or more substituents selected from the group consisting of—O—C₁-C₆alkyl, —S—C₁-C₆alkyl, amino, —C(O)-amino, —S(O)₂-amino, hydroxy,cyano, azido, and halogen; C₃₋₁₀ cycloalkyl optionally substituted withone or more substituents selected from the group consisting ofC₁-C₆alkyl, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl, amino, —C(O)-amino,—S(O)₂-amino, hydroxy, cyano, azido, and halogen; C₆-C₁₀ aryl optionallysubstituted with one or more substituents selected from the groupconsisting of C₁-C₆alkyl, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl, amino,—C(O)-amino, —S(O)₂-amino, hydroxy, cyano, azido, and halogen; 5 to 10membered heteroaryl optionally substituted with one or more substituentsselected from the group consisting of C₁-C₆alkyl, —O—C₁-C₆alkyl,—S—C₁-C₆alkyl, amino, —C(O)-amino, —S(O)₂-amino, hydroxy, cyano, azido,and halogen; and 4 to 10 membered heterocyclyl optionally substitutedwith one or more substituents selected from the group consisting ofC₁-C₆alkyl, —O—C₁-C₆alkyl, —S—C₁-C₆alkyl, amino, —C(O)-amino,—S(O)₂-amino, hydroxy, cyano, azido, and halogen.
 106. The compound ofclaim 105, wherein R⁵ is —S—C₁-C₆alkyl, —S—C₁-C₆ cycloalkyl, or —S-4 to10 membered heterocyclyl.
 107. The compound of claim 106, wherein R⁵ is—S—CH₃.
 108. The compound of claim 105, wherein R⁵ is —O—C₁-C₆alkyl,—O—C₁-C₆ cycloalkyl, or —O-4 to 10 membered heterocyclyl.
 109. Thecompound of claim 108, wherein R⁵ is


110. The compound of claim 108, wherein R⁵ is —OCH₃.
 111. The compoundof any one of claims 79-17 and 23-31, wherein: n is 0 or 1; Y² is —NH—;G is selected from the group consisting of —C(O)R⁴, —C(O)(CH₂)₀₋₃SR³,—C(O)(CH₂)₁₋₃R⁴, —C(O)OR³, —C(O)NR¹R², —S(O)₂R³, —C(═NR¹)R⁴, and—C(═NR)NR¹R².
 112. The compound of claim 111, wherein G is selected fromthe group consisting of —C(O)R⁴, —C(O)(CH₂)₀₋₃SR³, —C(O)OR³, —C(O)NR¹R²,—S(O)₂R³, —C(═NR¹)R⁴, and —C(═NR¹)NR¹R².
 113. The compound of claim 111or 112, wherein G is —C(O)R⁴.
 114. The compound of claim 111 or 112,wherein G is —C(O)(CH₂)R⁴.
 115. The compound of any one of claims 111 to114, wherein R⁴ is optionally substituted C₁₋₄alkyl.
 116. The compoundof claim 115, wherein R⁴ is C₁₋₄alkyl substituted with C₁-C₄ alkylthio.117. The compound of claim 116, wherein R⁴ is —CH₂SCH₃
 118. The compoundof claim 115, wherein R⁴ is C₁₋₄alkyl substituted with 5-10 memberedheteroaryl optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, and C₁-C₆ haloalkoxy.
 119. The compound of claim 118,wherein R⁴ is


120. The compound of claim any one of claims 111 to 114, wherein R isoptionally substituted 5-10 membered heteroaryl.
 121. The compound ofclaim 120, wherein R⁴ is 5-10 membered heteroaryl substituted withamino.
 122. The compound of claim 120, wherein R⁴ is


123. The compound of any one of claims 1 to 96, wherein G is—C(O)CH₂SR³.
 124. The compound of claim 123, wherein R³ is C₁₋₄alkyl.125. The compound of claim 123, wherein R³ is 5-10 memberedheterocyclyl.
 126. The compound of any one of claims 79 to 96 and 23-31,wherein G is —C(O)(CH₂)SCH₃.
 127. The compound of any one of claims 79to 96 and 23-31, wherein G is


128. The compound of any one of claims 79 to 96 and 23-31, wherein G is


129. The compound of any one of claims 79-96 and 102-110, wherein Y² is—S(O)₂—.
 130. The compound of claim 129, wherein G is optionallysubstituted C₆₋₁₀aryl.
 131. The compound of any one of claims 79-130,wherein Y¹ is CH.
 132. The compound of any one of claims 79-130, whereinY¹ is N.
 133. The compound of claim 79-81 and 83-132, wherein Q¹ and Q²are deuterium.
 134. The compound of claim 79, having the structureselected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 135. The compound of anyone of claims 1-134, wherein the pharmaceutically acceptable salt is analkaline metal salt or ammonium salt.
 136. The compound of claim 135,wherein the pharmaceutically acceptable salt is a sodium salt.
 137. Apharmaceutical composition comprising a therapeutically effective amountof a compound of any one of claims 1-136 and a pharmaceuticallyacceptable excipient.
 138. The pharmaceutical composition of claim 137,further comprising an additional medicament.
 139. The composition ofclaim 138, wherein the additional medicament is selected from anantibacterial agent, an antifungal agent, an antiviral agent, ananti-inflammatory agent, or an anti-allergic agent.
 140. The compositionof claim 139, wherein the additional medicament is a β-lactamantibacterial agent.
 141. The composition of claim 140, wherein theβ-lactam antibacterial agent is selected from Amoxicillin, Ampicillin(Pivampicillin, Hetacillin, Bacampicillin, Metampicillin,Talampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin,Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam(Pivmecillinam), Sulbenicillin, Benzylpenicillin (G), Clometocillin,Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin,Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathinephenoxymethylpenicillin, Pheneticillin, Cloxacillin (Dicloxacillin,Flucloxacillin), Oxacillin, Meticillin, Nafcillin, Faropenem, Tomopenem,Razupenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin,Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone,Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole,Cefininox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone,Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef,Cefixime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren,Cefetamet, Cefinenoxime, Cefodizime, Cefoperazone, Cefotaxime,Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten,Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran,Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428,MC-04,546, ME 1036, Ceftiofur, Cefquinome, Cefovecin, RWJ-442831,RWJ-333441, or RWJ-333442.
 142. The composition of claim 140 wherein theβ-lactam antibacterial agent is selected from Ceftazidime, Biapenem,Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Tebipenem pivoxil,Apapenem, or Panipenem.
 143. The composition of claim 140, wherein theβ-lactam antibacterial agent is selected from Aztreonam, Tigemonam,BAL30072, SYN 2416, or Carumonam.
 144. A method of treating a bacterialinfection, comprising administering to a subject in need thereof, acompound according any one of claims 1-136.
 145. The method of claim144, further comprising administering to the subject an additionalmedicament.
 146. The method of claim 145, wherein the additionalmedicament is selected from an antibacterial agent, an antifungal agent,an antiviral agent, an anti-inflammatory agent, or an antiallergicagent.
 147. The method of claim 146, wherein the additional medicamentis a β-lactam antibacterial agent.
 148. The method of claim 147, whereinthe β-lactam antibacterial agent is selected from Amoxicillin,Ampicillin (Pivampicillin, Hetacillin, Bacampicillin, Metampicillin,Talampicillin), Epicillin, Carbenicillin (Carindacillin), Ticarcillin,Temocillin, Azlocillin, Piperacillin, Mezlocillin, Mecillinam(Pivmecillinam), Sulbenicillin, Benzylpenicillin (G), Clometocillin,Benzathine benzylpenicillin, Procaine benzylpenicillin, Azidocillin,Penamecillin, Phenoxymethylpenicillin (V), Propicillin, Benzathinephenoxymethylpenicillin, Pheneticillin, Cloxacillin (Dicloxacillin,Flucloxacillin), Oxacillin, Meticillin, Nafcillin, Faropenem, Tomopenem,Razupenem, Cefazolin, Cefacetrile, Cefadroxil, Cefalexin, Cefaloglycin,Cefalonium, Cefaloridine, Cefalotin, Cefapirin, Cefatrizine, Cefazedone,Cefazaflur, Cefradine, Cefroxadine, Ceftezole, Cefaclor, Cefamandole,Cefininox, Cefonicid, Ceforanide, Cefotiam, Cefprozil, Cefbuperazone,Cefuroxime, Cefuzonam, Cefoxitin, Cefotetan, Cefmetazole, Loracarbef,Cefixime, Ceftriaxone, Cefcapene, Cefdaloxime, Cefdinir, Cefditoren,Cefetamet, Cefinenoxime, Cefodizime, Cefoperazone, Cefotaxime,Cefpimizole, Cefpiramide, Cefpodoxime, Cefsulodin, Cefteram, Ceftibuten,Ceftiolene, Ceftizoxime, Flomoxef, Latamoxef, Cefepime, Cefozopran,Cefpirome, Cefquinome, Ceftobiprole, Ceftaroline, CXA-101, RWJ-54428,MC-04,546, ME 1036, Ceftiofur, Cefquinome, Cefovecin, RWJ-442831,RWJ-333441, or RWJ-333442.
 149. The method of claim 147, wherein theβ-lactam antibacterial agent is selected from Ceftazidime, Biapenem,Doripenem, Ertapenem, Imipenem, Meropenem, Tebipenem, Tebipenem pivoxil,Apapenem, or Panipenem.
 150. The method of claim 147, wherein theβ-lactam antibacterial agent is selected from Aztreonam, Tigemonam,BAL30072, SYN 2416, or Carumonam.
 151. The method of any one of claims144-150, wherein the subject is a mammal.
 152. The method of claim 151,wherein the mammal is a human.
 153. The method of any one of claims144-152, wherein the infection comprises a bacteria selected fromPseudomonas acidovorans, Pseudomonas alcaligenes, Pseudomonas putida,Burkholderia cepacia, Aeromonas hydrophilia, Francisella tularensis,Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providenciaalcalifaciens, Providencia rettgeri, Providencia stuartii, Acinetobacterbaumannii, Bordetella pertussis, Bordetella para pertussis, Bordetellabronchiseptica, Haemophilus ducreyi, Pasteurella multocida, Pasteurellahaemolytica, Branhamella catarrhalis, Borrelia burgdorferi, Kingella,Gardnerella vaginalis, Bacteroides distasonis, Bacteroides 3452Ahomology group, Clostridium difficile, Mycobacterium tuberculosis,Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae,Corynebacterium diphtheriae, Corynebacterium ulcerans, Streptococcuspneumoniae, Streptococcus agalactiae, Streptococcus pyogenes,Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus,Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcusintermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcushaemolyticus, Staphylococcus hominis, or Staphylococcus saccharolyticus.154. The method of any one of claims 144-152, wherein the infectioncomprises a bacteria selected from Pseudomonas aeruginosa, Pseudomonasfluorescens, Stenotrophomonas maltophilia, Escherichia coli, Citrobacterfreundii, Salmonella typhimurium, Salmonella typhi, Salmonellaparatyphi, Salmonella enteritidis, Shigella dysenteriae, Shigellaflexneri, Shigella sonnei, Enterobacter cloacae, Enterobacter aerogenes,Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens,Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Yersiniaenterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Yersiniaintermedia, Haemophilus influenzae, Haemophilus parainfluenzae,Haemophilus haemolyticus, Haemophilus parahaemolyticus, Helicobacterpylori, Campylobacter fetus, Campylobacter jejuni, Campylobacter coli,Vibrio cholerae, Vibrio parahaemolyticus, Legionella pneumophila,Listeria monocytogenes, Neisseria gonorrhoeae, Neisseria meningitidis,Moraxella, Bacteroides fragilis, Bacteroides vulgatus, Bacteroidesovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroideseggerthii, or Bacteroides splanchnicus.